Immunity, ageing and cancer

Evelyna Derhovanessian; Rafael Solana; Anis Larbi; Graham Pawelec

doi:10.1186/1742-4933-5-11

Immunity, ageing and cancer

Derhovanessian, Evelyna; Solana, Rafael; Larbi, Anis; Pawelec, Graham 2008-09-24 00:00:00 Compromised immunity contributes to the decreased ability of the elderly to control infectious disease and to their generally poor response to vaccination. It is controversial as to how far this phenomenon contributes to the well-known age-associated increase in the occurrence of many cancers in the elderly. However, should the immune system be important in controlling cancer, for which there is a great deal of evidence, it is logical to propose that dysfunctional immunity in the elderly would contribute to compromised immunosurveillance and increased cancer occurrence. The chronological age at which immunosenescence becomes clinically important is known to be influenced by many factors, including the pathogen load to which individuals are exposed throughout life. It is proposed here that the cancer antigen load may have a similar effect on "immune exhaustion" and that pathogen load and tumor load may act additively to accelerate immunosenescence. Understanding how and why immune responsiveness changes in humans as they age is essential for developing strategies to prevent or restore dysregulated immunity and assure healthy longevity, clearly possible only if cancer is avoided. Here, we provide an overview of the impact of age on human immune competence, emphasizing T-cell-dependent adaptive immunity, which is the most sensitive to ageing. This knowledge will pave the way for rational interventions to maintain or restore appropriate immune function not only in the elderly but also in the cancer patient. in animal models and is supported by epidemiological Introduction Cancer is largely a disease of older people; the median age evidence, such as increased frequency of certain cancer for cancer diagnosis in industrialised countries is types in immunosuppressed individuals [4,5]. Here, we approaching 70 years of age and is expected to increase discuss the effects of age on immune-cell development [1]. This can be due to different reasons, such as increased and function, as well as the dynamics and turnover of duration of carcinogenesis or the susceptibility of aging immune cells in the elderly, and speculate as to whether cells to environmental carcinogens [2,3]. Another mecha- many of these changes are the result of persistent chal- nism responsible might be reduced immune function, lenge by a range of antigen types including cancer anti- "immunosenescence", in the elderly. The importance of gens. Immune correlates with response to vaccination and the immune system in preventing tumor formation, mortality and possible interventions to restore appropri- termed immunosurveillance, has been repeatedly shown ate immunity and enhance responses to vaccination in the Page 1 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 elderly are also discussed. This will be of crucial impor- Studying immune cells directly ex vivo, as well as in culture tance not only for vaccination against common pathogens models of ageing in vitro, has contributed to our under- such as influenza [6], but for the increasing application of standing of age-associated changes in human T-cell-medi- immunotherapy for cancer in the elderly. Especially in the ated immunity. However, exactly which factors are most latter case, the mild or absent side effects of immuno- important in immunosenescence and what causes these therapy compared to chemotherapy of cancer may make age-associated changes remain largely unclear. Accumu- this approach particularly desirable in the frail older can- lating data initially unexpectedly implicated infection cer patient. with persistent herpesviruses, particularly cytomegalovi- rus (CMV), as contributing to the age-associated changes Impact of aging on immune parameters observed in many studies of human immune ageing [18- In elderly people, the ability to respond in a versatile way 22]. By analogy, long-term exposure to other persistent to pathogens, and potentially to cancer, is reduced due to stimulating agents, possibly parasite antigens rather than dysregulated immunity, a state known as immunosenes- CMV, especially in developing countries, as well as dysreg- cence. This is characterized firstly by low numbers of naïve ulated responses to autoantigens and cancer antigens, T cells in the peripheral blood [7] and probably also in may yield similar effects. Clearly, more detailed knowl- other immune organs such as the lymph node [8], which edge of the reasons for immune dysfunction at advanced is robustly observed in different human populations [9]. age and development of strategies to prevent or reverse There is a corresponding reduction in the diversity of the this should contribute to maximizing healthy lifespan for naïve T-cell receptor (TCR) repertoire, which helps to the ever-growing numbers of elderly people in industrial- explain the decreased ability of the elderly to resist infec- ized and, increasingly, in industrializing countries. tions to which they were not previously exposed, or to respond to the de novo appearance of tumor antigens. Sec- Immune-cell development ond, although the number of memory T cells increases, The cells of the immune system turn over rapidly, so com- there is a decrease in the diversity and functional integrity promised production or function of haematopoietic stem + + of both the CD4 and CD8 T-cell subsets [10,11] which cells (HSCs) would affect all aspects of immunity down- contributes to the decreased ability of the elderly to stream [23]. There is evidence for an association between respond adequately to re-infection or to retain memory HSC decline and longevity [24] probably due to differ- for cancer antigens expressed by relapsing tumors. Moreo- ences in DNA damage repair [25,26]. Purified HSCs from ver, the ability to respond appropriately to persisting old mice have less ability to reconstitute haematopoiesis infection or persistent exposure to other antigen sources, [27]. It has been recently suggested that the observed age- such as cancer antigens, may also be compromised, a associated skewing of hematopoiesis away from lym- process sometimes termed "immune exhaustion" [12]. phocyte generation may be one of the factors contributing to increased cancer occurrence with age [28]. There is also The focus of much research on immunosenescence has a gradual decline in the ability of mouse HSCs to progress been T cells, mainly because antigen presentation by den- through the various B-cell differentiation stages, partly dritic cells (DCs) generally seems well-retained in the eld- reflecting microenvironmental changes. These may erly [13], and because appropriate B cell [14] function involve altered production of interleukin-7 (IL-7) by stro- depends on helper T cells. This is not to imply that non- mal cells [29]. Changes at the level of T-cell progenitors clonotypic immunity is entirely resistant to age-related also contribute to age-associated deficits in mice [30]. In changes, or unimportant, but the alterations to natural any event, age is likely to impact both on HSCs and the killer (NK) cells and other innate immune cells [13] seem niche environment that determines their fate (Figure 1). to be less marked than those seen with T cells. Nonethe- less, it has been reported that NK cell status can predict Although even the very elderly can retain some degree of morbidity and mortality in the elderly, emphasizing the thymic function [31], thymic involution which represents importance of innate as well as adaptive immunity in the next hurdle that a T-cell progenitor must overcome in ensuring healthy longevity and possibly cancer resistance order to develop into a mature naïve T cell. That this could [15]. In addition, and at least partly because of innate be clinically important in cancer is demonstrated in a immune activity, the levels of pro-inflammatory factors study of age-dependent glioma-associated mortality, in are commonly increased in the elderly and are associated which the numbers of CD8 recent thymic emigrants with negative effects on health [16]. Together, these accounted for the effect of age on clinical outcome [32]. changes contribute to morbidity and mortality, and are However, assessing immune reconstitution after HSC associated with poor responses to vaccination against transplantation has demonstrated exceedingly low levels pathogens such as those causing influenza and pneumo- of thymic activity after the age of around 40 years [33]. nia [17], leading to decreased quality of life and increased Exactly why thymic involution occurs remains unclear. health-care burdens in later life. Because the most marked (but not the only [34] changes Page 2 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 Impa Figure 1 ct of ageing on immune cell development Impact of ageing on immune cell development. Genetic and environmental influences modulate age-associated altera- tions to the number and function of HSCs in the BM, resulting in skewed production of leukocytes. Reduced production of T cell progenitors, together with age-associated thymic involution, results in a relatively larger impact of age on T cells than on other leukocytes. to thymic size and structure occur around puberty, it has ences, with less peripheral blood [41] and follicular DCs been suggested that increased levels of sex hormones con- [42]. Chemotaxis and phagocytosis may be impaired in tribute to causing thymic involution; thymic output of DCs, as well as neutrophils [13], from the elderly [43]. naïve T cells can increase in both mice and humans fol- DCs from young and elderly people are reported to stim- lowing androgen ablation [35,36]. Nevertheless intrinsic ulate naïve CD8 T cells equally well, but those from the defects in the commitment of haematopoietic stem cells elderly may fail to stimulate naïve CD4 T cells properly to the lymphoid lineage [37] and the migration of T-cell [43], perhaps due to altered signal transduction pathways progenitors into the thymus have also been implicated in involving phosphoinositide 3-kinase signalling [44]. In this process [38]. Whatever the reason, it is clear that cancer, the effect of the tumor on the APC may enhance major age-associated changes to the thymus and greatly these deficits [45]. Many active immunotherapy protocols decreased output of naïve T cells are observed in both for cancer patients rely largely on DCs to be recruited to mice and humans (Figure 1). The elderly must therefore the site of vaccination and take up the vaccine antigen. increasingly rely on naïve T cells already previously pro- Reduced DC numbers as well as their chemotactic and duced and the small numbers possibly still being pro- phagocytic activity in the elderly might represent another duced. The presence of cancer, or particularly the hurdle to be overcome in developing successful vaccina- treatments applied as cancer therapy, are also likely to fur- tion strategies for elderly cancer patients. ther compromise any residual thymic function [39]. One very good example of the interplay between innate Innate-adaptive immune interactions and adaptive immunity is illustrated by γδ-T cells [46], In the next stage in T-cell-dependent immunity, naïve T which also show age-associated alterations. These are able cells must be activated by appropriate contact with anti- to recognize phosphoantigens present on cancer cells and gen-presenting cells (APCs), such as DCs (Figure 2). have anti-tumor activities, as well as other functions, such Although DCs seem to be only subtly different in the eld- as anti-CMV activity [47]. Their numbers rise from birth to erly in many respects [40], there are quantitative differ- puberty and gradually decrease again beyond 30 years of Page 3 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 A Figure 2 ge-associated changes to DCs Age-associated changes to DCs. Reduced numbers and functions of of DCs, together with reduced numbers of naïve T cells in the periphery of aged individuals further conspire to ensure that T cell function is depressed in the elderly due to the relative decrease in T helper cell activation. age, and they show functional alterations [48,49]. A func- varying proportions of the different T-cell subpopulations tional analysis in young/adult and middle aged donors in each individual, which cannot be assumed to manifest revealed that effector/memory γ9/δ2 CD27- T cells are identical age-related changes. increased after in vitro culture in the presence of specifi- cally stimulatory isopentenylpyrophosphate and IL-2 for There is no evidence for alterations to the actual structure 10 days. In contrast, this did not occur when using cells of TCRs or co-stimulatory receptors with age, but it is from old subjects, confirming a lack of naive and central likely that their assembly into functional units is compro- memory cells responding to IL-2 [50,51]. In these mised, leading to alterations in the assembly of the signa- respects, γδ T cells behave quite similarly to conventional losome (Table 1). One major factor that influences TCR αβ T cells, as discussed in the next section. assembly is cell membrane fluidity, as first suggested many years ago [52]. However, this changes according to T-cell function and ageing systemic fatty-acid availability, as illustrated by infusing Changes at the single-cell level lipids into young volunteers [53], and not necessarily as a To mediate an adaptive immune response, T cells must result of ageing. Nonetheless, the increased levels of cho- interact with functional APCs, become activated and lesterol which occur commonly in the elderly might well undergo extensive clonal expansion, followed by clonal contribute to age-associated deficits in T-cell signalling contraction. Alterations in either the number or the struc- [54]. High cholesterol levels are also found in some can- ture of cell-surface receptors, as well as their location in cers, at least before the metabolic dysregulation caused by the membrane, and, once assembled, their intracellular the tumor results in their lowering as the disease signalling pathways, could all contribute to the final out- progresses (see, for example, [55,56]). come of each T-cell-DC interaction. Studies have focused on alterations in signal transduction as well the formation Although the number of TCR molecules per T cell does of signalling domains (such as the immunological syn- not seem to change with age [57], there are clear altera- apse). The interpretation of much of the published data is, tions in the number and balance of receptors that mediate however, complicated by the use of samples consisting of positive or negative co-stimulatory signals. Decreased or Page 4 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 absent expression of the most studied of these cell-surface cells, are not well documented. For example, the well- molecules, CD28, is commonly referred to as a biomarker known age-associated decrease in activation of the SRC- for immunosenescence [58], because highly differentiated family protein tyrosine kinase LCK, which is one of the - + CD28 T cells, especially within the CD8 T-cell subset, earliest events after TCR ligation and thought to be essen- tend to accumulate in the peripheral blood of the elderly tial for T-cell stimulation, was recently shown to be crucial and because CD28 expression is lost after extended cul- only for naïve T cells (at least in mouse CD8 T cells) [65], ture in vitro as T cells undergo differentiation and enter a of which the elderly simply possess fewer. state of replicative senescence [58]. Studies of cultured T cells have confirmed that decreases in CD28 expression Changes at the cell population level do occur within monoclonal populations as they undergo Naïve T cells express CC-chemokine receptor 7 (CCR7) clonal expansion and progress through their finite and leucocyte common antigen isoform CD45RA [66] lifespan, excluding the possibility that a small population and have long telomeres [67], whereas many memory T - + of originally CD28 cells overgrows the CD28 cells [59]. cells express the alternative splice variant CD45RO, have Nonetheless, the definition of such changes as biomarkers lost CCR7 and have shorter telomeres [68] suggesting an of immunosenescence remains problematic, because, for extensive proliferative history due to lack of telomere example, CD28 is downregulated by tumour-necrosis fac- maintenance. The advent of polychromatic flow cytome- tor (TNF) [60] and upregulated by IL-12 [61], not neces- try is facilitating the ever-finer ex vivo dissection of differ- sarily associated with senescence. It has also been difficult ent T-cell subpopulations and the changes in their to establish whether the much-investigated altered signal proportions with age. The best biomarker of immune age- transduction pathways in T cells are a result of an altered ing remains the relative levels of naïve T cells (defined as + + + + + balance of expression of positive and negative co-stimula- CD45RA CD27 CD28 CD62L CCR7 ) and memory cells tory receptors [62,63], determining the final outcome – (with a wide range of other phenotypes [69] and which activation, anergy or apoptosis of the T cell. Further stud- also exhibit age-related differences in TCR diversity, tel- ies on clonal populations in culture should facilitate dis- omere lengths and various other factors). To mount an tinguishing between changes caused by altered adequate response, a broad TCR repertoire must be main- proportions of cell subsets and changes within the same tained by ensuring the continuing presence of a diverse clones at different times; a first global gene expression population of T-cell clones, but this decreases with age. At analysis of early and late passage T-cell clones has revealed least for CD4 T cells, this may occur quite suddenly, with a wide range of differentially expressed genes, including TCR diversity well maintained up to the age range of those encoding proteins involved in signal transduction 60–65 years, despite the marked decrease of thymic out- and apoptosis [64]. Regarding TCR signalling in young put. However, repertoire diversity in 75–80 year olds is and old T cells, even here, the differences between naïve severely reduced [10] and probably contributes to the + + and memory T cells, as well as between CD4 and CD8 T poor responses to infection and vaccination in this age Table 1: Impact of age-associated signalling changes Features altered Resulting altered mechanism Cholesterol level Signalling molecule recruitment [135] Membrane fluidity Protein interaction [54] Lipid raft functions Early signalling/immune synapse formation [135] Calcium influx Induction of T cell activation Phosphatase activity Control of negative signalling PTK (Lck) activity Phosphorylation of LAT [57,135] LAT phosphorylation Activation of LAT-associated molecules MAP Kinase activation Cellular activation/survival [57,135] Cytoskeleton rearrangement Cell-cell contact/Immune synapse formation Translocation of transcription factors Induction of gene expression CD28 expression T cell costimulation/anti-apoptotic signals [58] KIR expression Formation of an activation platform KLRG-1, CD57, PD-1 expression Induction of T cell activation [92,158] For activation, T cells require sustained physical contact with APC. This feature is altered with age due to changes in the integrity of the membrane. Several signalling molecules fail to be activated with age, including PTK and adaptor proteins such as LAT. Calcium metabolism is altered, partly due to impaired PLCγ-1 phosphorylation. The alterations including lipid raft functions influence MAP Kinase activation and cytoskeletal rearrangements, together leading to differential activation and translocation of transcription factors such as NF-κB, NF-AT and AP-1 into the nucleus. This directly affects T cell clonal expansion due to decreased IL-2 production. Unbalanced negative signalling involving inhibitory receptors such as KIR2DL2 or Natural Killer Receptors contribute to reduce activation. PTK: protein tyrosine kinase; LAT: linker for activation of T cells; MAPK: Mitogen activated protein kinase; KIR: inhibitory killer immunoglobulin-like receptors; PLCγ-1: Phospholipase C-gamma 1. Page 5 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 group (Figure 3). The likely clinical implications of this cell subsets were proliferating and whether the rate of are reflected in the close correlation between the diversity expansion was different in people of different ages. Pio- neering work in which deuterated glucose is incorporated of the repertoire and remaining survival time in very old people [11]. One explanation for these events could be into dividing lymphocytes to distinguish the fraction of that because T cells are maintained in a state of constant the pool that proliferates during the labelling time is tech- turnover in the body, which is either antigen driven or nically challenging but very informative in humans and homeostatic, replicative senescence (proliferative exhaus- has now been applied to T cells, B cells and NK cells. In tion) occurs [70]. In cell culture, CD4 T cells become naïve, memory and regulatory T-cell subsets, label uptake more susceptible to apoptosis at this time of proliferative and loss occurs rapidly but at different rates in each sub- exhaustion [71], whereas CD8 T cells become apoptosis set, thus indicating divergent rates of cell division, with resistant [72]. The implication of these results is that in regulatory T cells proliferating most rapidly [74]. How- + + vivo, CD8 T cells would accumulate and CD4 T cells ever, the only substantial difference between young and + + + would be lost by clonal deletion, and the CD4 :CD8 T- old donors is that the CD8 memory T cells have a much cell ratio would therefore change. There is indeed evi- longer half-life than any other subset in the elderly, but T cells in vivo, and for dence for the accumulation of CD8 not in the young [75]. These results are consistent with an their correlation with poor outcomes to vaccination and accumulation of CD8 T memory cells in the elderly. In B with mortality, as discussed in more detail below. cells, there are also only slight differences between young and old individuals, with memory B cells turning over Immune cell dynamics and turnover more rapidly than naïve B cells [76], whereas in NK cells, Despite decreased thymic output of T cells, in healthy peo- the production and proliferation rates were lower in the ple, the overall number of T cells in the periphery remains elderly than in the young [77]. Nonetheless, B cell mem- remarkably constant at different ages, although there may ory may be maintained for a very long time; thus, it has be an association between slightly lower levels of both been recently shown that individuals who survived the + + CD4 and CD8 cells and mortality at 10-year follow-up Spanish flu (H1N1) still have specific antibodies 90 years [73]. Until recently it was impossible to determine which after the epidemic. These donors still possess circulating B cells that secrete antibodies that binding the respective recombinant haemagglutinin protein [78]. Given the high measured levels of peripheral T-cell turno- ver, it is not surprising that their proliferative potential eventually becomes exhausted; these exhausted cells are characterized by a lack of CD27, CD28 and telomerase expression [79], and by having short telomeres [80]. Memory T-cell turnover may not only result in an eventual loss of the cells, but also in an active acquisition of sup- pressive activity as demonstrated in vitro [81] and more recently in vivo, suggesting that development of regulatory T cells (Tregs) from terminally-differentiated CD4 cells can take place [74]. Tumor antigens as the driving force in this process might account for the commonly-observed H th Figure 3 y e h pot uh man lifespan etical model for the evolution of T cell immunity over higher levels of Tregs in cancer patients, which are Hypothetical model for the evolution of T cell immu- believed to be a bad prognostic sign, and to interfere with nity over the human lifespan. Age-associated changes to immunotherapy [82]. Mechanisms therefor may include T cell immunity result in decreasing proportions of naïve cells competition for antigen on the DC surface, or altered and increasing proportions of memory cells over the lifespan. TCR repertoire diversity is well-maintained at least until the cytokine secretion patterns [59]. At least for pathogens end of the reproductive period, when repertoire shrinkage establishing only acute infection, antigen seems not to be occurs rapidly. This point is reached as the number of differ- required for the constant turnover of specific memory T ent clonal expansions caused by persistent pathogens, as cells. In mice after clearance of acute viral infection, mem- demonstrated for CMV, plateaus and then decreases. Loss of ory T cells persist for the lifetime of the animal and also repertoire diversity in memory cells is not paralleled by their undergo clonal expansions and accumulate even in the decreased numbers; on the contrary, these continue to rise absence of the original antigen [83]. Thus, T-cell clonal as dysfunctional cells accumulate, possibly a compensatory exhaustion may be an intrinsic characteristic of adaptive mechanism. At this time also, responses to vaccination, as immunity, which still occurs even in the absence of documented with influenza vaccination, are much less effec- chronic infection [84]. However, the biological norm is tive than at earlier time points. likely to be chronic infection; in humans, mostly herpes Page 6 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 viruses, especially CMV and in CMV-negative elderly indi- The apoptosis-resistant cells that accumulate in both old viduals, Epstein-Barr virus (EBV), may be the main agents mice and humans may be dysfunctional in several ways. T cells to exhaustion [85]. In different envi- driving CD8 In young mice, the number of T cells staining with soluble ronments, possibly where EBV and CMV are not so preva- MHC/peptide multimers loaded with influenza-virus lent, other pathogens may play a similar role. Analogous epitopes is very similar to the number of T cells producing phenomena of clonal exhaustion and senescence may interferon-γ (IFNγ) on antigen stimulation, indicating also occur in HIV disease [86] and autoimmunity [87,88], that essentially every antigen-specific cell present is able to and, as we argue here, cancer. Although the proliferative respond to antigen. However, in old mice, the number of reserve of T cells is high, at least until telomere erosion tetramer-positive cells exceeds the number of IFNγ-pro- reaches its critical limit (termed the Hayflick limit), being ducers, indicating that a proportion of the antigen-specific approximately 70 population doublings for CD4 T cells cells fails to respond. This is quite similar to the situation [70], the old idea that T-cell clonal exhaustion leads to in very elderly individuals who accumulate large clonal clonal attrition and has clinical consequences has stood expansions of CMV-specific T cells, the majority of which the test of time. The clinical consequences may be broad are dysfunctional (or anergic). Longitudinal studies of and impact not only on those very advanced in years, as elderly Swedes have established that individuals with the discussed in the next section. largest accumulations of clonally expanded CD8 T cells, most of which are CMV-specific and have a mature phe- - - + + Immune biomarker correlates with response to vaccination notype (CD27 CD28 CD57 KLRG1 ) [92,93], have a and mortality shorter remaining survival time than people of the same Establishing reliable biomarkers identifying T-cell subsets age with less of these cells at baseline. In CMV-positive and determining which are the most relevant to healthy subjects, the number of different clonal T-cell expansions ageing and adequate responses to vaccination requires increases from middle age to old age and decreases in the longitudinal studies following the same individuals over terminal phase of life, resulting in a highly significant cor- time and correlating test parameters with clinical outcome relation between the number of T-cell clones and survival (such as mortality, pathology and vaccination responses). of the individual [11]. This finding suggests that eventual Cross-sectional studies have the disadvantage that the loss of control of CMV infection after a lifetime of immu- young and old populations compared will have differed nosurveillance may indeed be a cause of mortality in this tremendously in their previous exposure to environmen- elderly population (Figure 4). Whether this will be a gen- tal factors of all kinds, and probably, also genetic consti- eral finding in other populations remains to be seen. tution. However, so far, most human studies have been Clonal expansions of CD8 T cells are also found in old cross-sectional, and because of logistical constraints we mice; whether this is antigen independent (random TCR cannot even be sure whether acute infectious complica- usage; homeostatic proliferation) or antigen driven may tions are really more severe in the elderly due to impaired depend on the pathogen environment [94]. Thus, innate and adaptive immunity or due to other factors. although antigen driven, especially CMV-stimulated, T- Apparently simple questions such as the correlation of cell clones may be the type most frequently found in aged immune status with outcome of vaccination in the elderly humans, this finding suggests that there are multiple, cannot yet be answered definitively. Correlations between independent mechanisms that can contribute to age- the presence of certain T-cell subpopulations and poor altered CD8 T-cell homeostasis. All these findings suggest that dysfunctional, end-stage differentiated cells may responses to vaccination against influenza virus have, + - however, been reported. Excessive CD8 CD28 T cells cor- accumulate in various physiological situations [95]. To relate with poor responsiveness, whereas, counter-intui- what extent this process is amplified in CMV carriers who + + tively, frequencies of CD4 memory T cells, regardless of are also cancer patients, and not only for CD8 but also CD28 expression, do not [89]. In mouse models, the virus CD4 T cells as well as possibly components of innate is cleared from the lungs more slowly in old than young immunity [13,96] must be further investigated. This mice, correlating with a delayed and decreased peak of notion is consistent with the hypothesis that such CD8 cytotoxic T-cell production. Thus, cellular responses are cells fill the "immunological space", thereby decreasing crucial for controlling the virus but do not function ade- immune competence and raising the possibility of inter- quately in old animals; this appears to be likely in humans vening to restore appropriate immunological function too [90]. In mice, cell transfer experiments demonstrated [97,98]. As we learn more about the dysfunctional status that it was both the old environment and the old cells that of these cells, in terms of basic biochemical functions contributed to the problem – that is, even young func- [99,100] and receptor signalling [101] we may begin to tional T cells do not respond properly when transferred to identify biomarkers that can be used in monitoring ther- an old environment (and neither do old T cells when apy success [102,103]. There is some evidence for the transferred to a young environment) [91]. existence of such "exhausted" cells in cancer patients [104,105]. Whether the accumulation of dysfunctional Page 7 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 Decreasing Figure 4 regenerative reserve in immunosenescence Decreasing regenerative reserve in immunosenescence. Hypothesis: In the elderly, dysfunctional, often CD8+ CMV- specific T cells accumulate because apoptotic pathways are compromised. Vital memory cells are eventually lost by clonal attri- tion (clonal exhaustion). Loss of memory cells for previously encountered pathogens contributes to morbidity and mortality. Thus, decreased clonal heterogeneity correlates with mortality in longitudinal studies. Because T cell homeostasis maintains constant numbers of T cells in the periphery, even the age-associated decreased thymic-output of naive cells is blocked, and the shrink- age of the naive T cell repertoire contributes to increased susceptibility to newly-encountered infectious diseases. IM, infec- tious mononucleosis; PD, population doublings. cells can influence response to therapy, in particular to ceptible to deleterious changes with age, but innate immunotherapy in cancer patients, remains to be responses tend to be better-preserved [108]. In fact, reten- explored; very few approaches to this question have been tion of strong inflammatory responses with age, but now made so far, but a limited literature exists in animal mod- in the absence of the counterbalancing and beneficial els. effects of the adaptive responses that they normally amplify at younger age may even enhance immunopa- Cancer immunity and ageing thology and carcinogenesis. This might also help to The extent to which tumors are controlled by immunity is explain the genetic component of certain cancers in which controversial. Nonetheless, there is clear evidence for the inflammation is well-established as an amplificatory fac- immunogenicity of cancer cells and large numbers of can- tor [109]. On the other hand, tumors may be less aggres- cer immunotherapy trials have shown beyond reasonable sive in the elderly, as seen in breast, lung, colon and other doubt that T cells recognizing tumor antigens can be sites in very old people and centenarians, partly because amplified in many patients. The calculated frequency of of the lower inflammatory status of "successfully aged" cells responding to a vaccine antigen (MAGE-3) in people, which also decreases the ability of the stromal tis- melanoma suggests that responding T cells must divide a sue to support tumour growth and angiogenesis [110]. large number of times to generate the observed number of responding cells and to be effective in patients [106]. This According to these considerations, young and old individ- extreme requirement for clonal expansion might well be uals will most likely require different treatment partially responsible for the lack of success of many cancer approaches, which could solve some of the problems of vaccination trials, due to the phenomenon of replicative treating geriatric cancer patients with other, more tradi- senescence in T cells [70]. tional, modalities. Cancer could be less responsive to chemo- and radiotherapy in the elderly, and this might be Limited studies in preclinical animal models have indi- because the immune system is less effective in the elderly, cated age-associated alterations in tumor immunity and following the notion that even responses to chemo- and therapeutic responses. Thus, in a mouse breast cancer radiotherapy require an intact immune system [111]. In model, there are effective anti-cancer immune responses the few animal models investigated thus far, cancer in young animals which are mostly mediated by T cells, immunity successful in young individuals is mostly less whereas the (less effective) responses in old animals pri- effective in older ones. Young mice injected with highly marily rely on innate immunity [107]. This could be a immunogenic tumors such as chemical- or radiation- general finding, because adaptive immunity is highly sus- induced sarcomas controlled the tumor better compared Page 8 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 to old mice. In contrast, tumors with weak immunogenic- BCR repertoire diversity due to clonal deletions, decreased ity, like B16 melanoma, were more aggressive and grew thymic and bone marrow output, and accumulations of better in young animals compared to old (reviewed in dysfunctional cells. In addition to avoiding over-eating [112]). Sometimes, decreased efficacy in old mice can be and ensuring that sufficient exercise is taken, what else can compensated for by increasing costimulation [113,114], be done to reconstitute immunity at old age? which is focussing efforts on improving adjuvants for the Restoring naive T-cell number and function purpose of better vaccination results in the elderly in gen- eral. This may be particularly important given the possible Given the paucity of naïve T cells in the elderly, enhance- synergistic effects of ageing and cancer on DC function, ment of thymic output is likely to be a first requirement such that the relative contribution of DC dysfunction may for maintaining or restoring their effective immunity. be greater in cancer than in healthy ageing [115]. How- However, although in a contrived experimental situation ever, as with other aspects of the complex interactions in mice, neonatal thymi grafted under the kidney capsule between cancer and ageing, it will be difficult to generalize exported the same numbers of T cells regardless of from one system to another. Thus, it has already been whether the peripheral pool was oversupplied (by thymic demonstrated that some immunotherapies are actually grafts) or undersupplied (due to neonatal thymectomy) effective only in old but not young animals [116], imply- [121], feedback mechanisms maintaining T-cell homeos- ing that patient-individualized therapies will have to take tasis in humans would be expected to prevent any residual the immunological age of the individual closely into thymic output due to the accumulated dysfunctional account. For this, it will clearly be necessary to differenti- CD8 T cells present in the periphery. This may be consist- ate between chronological age and the "functional" age of ent with age-associated decreases in thymic output of + + immunity, as could be based on the constellations of CD8 T cells being more marked than CD4 T cells, at least immune markers making up the "immune risk profile" or in mice [122]. Such CD8 T-cell accumulations could be the modified set of markers investigated by Hirokawa et reduced or eliminated by identifying ways of specifically al. mentioned above [105]. targeting the dysfunctional subset [98]. Efforts directed at thymic reconstitution could then follow. Possible interventions and improved vaccination strategies As discussed above, immunosenescence results from mul- In mice, it was reported that transplantation of aged invo- tifactorial processes that act on all components of the luted thymi into juvenile recipients led to reconstitution immune system and some approaches to reconstitute of the structure and function of the thymus [123]. Moreo- appropriate function have already been mentioned. ver, transplantation of cultured thymic fragments to Recent results from studies on long-lived non-human pri- patients with DiGeorge syndrome who lack a functional mates maintained on a calorie-reduced diet showing thymus, has been carried out successfully [124] and may improved maintenance and/or production of naïve T also be a conceivable approach to restore naive T-cell cells, better T-cell function and reduced pro-inflammatory numbers in the elderly. The use of T-cell survival factors, status [117], and the possible beneficial effects of moder- such as IL-7, has been explored in mice and monkeys, and ate exercise [118], serve to emphasize the continued rele- local delivery of this cytokine to the thymus by implanta- vance of common-sense medical advice in "anti-ageing" tion of genetically engineered stromal cells secreting it medicine as applied to immunosenescence. Although as may be a way of avoiding systemic effects [125]. Sex ster- ageing proceeds, the T- and to some extent B-cell compart- oid ablation in men undergoing therapy for prostate can- ments seem to be particularly susceptible to senescence, cer is reported to result in increased numbers of NK cells and other components of innate immunity are circulating naïve T cells, but this approach is obviously also affected. As mentioned above, some limited data do not generally applicable to the majority of elderly people point to a crucial impact of NK-cell status on resistance to [35]. More recently, other factors such as keratinocyte infectious disease and hence healthy longevity [15], as growth factor have been shown to improve thymic output well as being implicated in the outcome of influenza vac- in old mice [126]. Thymic epithelial cells, which are cination [119]. It is likely that NK cells also play a role in required to support thymocyte maturation, undergo determining the outcome of cancer immunotherapy apoptotic death in the aged thymus, through a pathway [103]. Clearly, it is not only the T-cell status and/or CMV involving interactions between FAS and FAS ligand. status of elderly subjects that affects the outcome of vacci- Because age-associated thymic involution is reported not nation [120], but also the pre- (and post-) vaccination to occur in aged FAS-deficient mice [127], blocking this NK-cell status [119] (although how much the latter is pathway locally in the thymus might also contribute to affected by CMV is not yet clear). It is therefore imperative retaining thymic functionality. The same may apply to that these studies are extended and repeated in different transforming growth factor-β2 (TGFβ2), as greater thymic populations. Nonetheless, the most severe clinical impact cellularity and higher levels of naive T cells are seen in old is likely to remain primarily the result of loss of TCR and TGFβ2-deficient mice compared to old wild-type mice Page 9 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 [128]. T cells that have undergone clonal exhaustion after ations of IL-6, for example, with frailty [139], reducing the chronic viral infection also express the B7-family receptor levels of such mediators would nonetheless be beneficial named programmed cell death-1 (PD1), that inhibits co- not only for improving immune status, via improved anti- stimulatory signals [129]. It has been suggested that gen presentation [140], for example, but also by its effect blocking PD1-mediated signalling could lead to on many other organ systems. Given the contribution of improved T-cell function [130]. inflammation to carcinogenesis, there may well be benefit of using anti-inflammatories in this context as well. Nutri- It is too early to say whether any of these approaches can tional intervention by caloric restriction, that was shown be translated to human therapy. It is possible that, among to improve the immune response in rodents [141], has its other effects, CMV has a role in reducing thymic out- also been shown to delay T cell immunosenescence in put: at least in clinical human HSC transplantation, out- non human primates, preserving the number and func- put of naïve T cells is reduced by CMV infection [131]. tion of naive T cells [117]. Steps taken to reduce CMV infection might therefore also benefit naïve T-cell production. Antigenic load Given the initially quite unexpected impact of infection Nutrition and inflammation with persistent herpesviruses on immunity in the elderly Interventions in nutrition, which are relatively easy to [19] strategies to reduce the infectious antigenic load carry out, could have a larger impact on immune function would seem to offer a reasonable approach to restoring than commonly appreciated, even in donors selected for appropriate immunity. The Swedish OCTO/NONA longi- very good health [132]. Vitamin E supplementation has tudinal studies [142] have revealed several changes in received much attention, and was recently reported to immune parameters predicting mortality at 2, 4 and 6 year reconstitute immunological synapse formation, especially follow-up, and summarized in what we have designated in CD4 naïve T cells of old mice [133]. However, many the IRP [143]. This is a cluster of immune biomarkers nutritional interventions could be viewed more as correct- which may be informative in several elderly populations ing poor diet, or reducing an inappropriately rich diet, but [144,145], as well as in other circumstances, for example, this alone could have a major impact on immunity in the for the occurrence of infections after HSC transplantation elderly. Given the notion that increased basal levels of [146] and autoimmunity [88]. An initially surprising find- inflammation and frailty in the elderly are intimately ing was the association of the IRP in the elderly with CMV related, anti-inflammatory nutritional interventions infection [147], but not with morbidity [148], which is could be useful [16]. Modulating lipid intake would be a consistent with the effect of persistent herpesvirus infec- possibility in this context, using, for example, conjugated tions on immunity. A recent study [149] has also shown a linoleic acid, which can result in decreased pro-inflamma- progressive accumulation of HSV-specific T cells with a tory cytokine secretion and which can increase the success central memory phenotype in old mice. However the con- rates of hepatitis B vaccination in the elderly [134]. As dis- tinuous administration of antiviral drugs did not alter the cussed above, the lipid environment strongly influences course of this accumulation of T cells. These results sug- T-cell function, and alterations in membrane fluidity gest the possibility that, at least in this experimental affect lipid raft and immunological synapse formation model, T cells expansions arise as a consequence of age- [52,135]. Human high-density lipoprotein extracts accu- associated homeostatic disturbances rather than repeated mulated cholesterol from lipid rafts, resulting in increased antigenic stimulation. Nevertheless, the direct influence TCR signal transduction and T-cell activation [136]. of CMV and other herpes viruses as a major driving force in T cell immunosenescence cannot be excluded. Thus, Use of non-dietary anti-inflammatory agents to decrease interventions targeting these viruses or the accumulated levels of IL-6, TNF and IL-1 may also assist in rebalancing dysfunctional memory cells specific for them [92], may be immunity; to this end, it might be possible to use rela- of clinical benefit both directly against viral infection and tively innocuous agents, such as statins, that are already in terms of improving responses to vaccination. The same being used extensively in the elderly to treat autoimmu- principle may apply to other human populations in areas nity and other diseases [137]. In particular, the level of IL- of differing pathogen load, for example parasitic infec- 6 was found to be an independent predictor of mortality tion, rather than herpesvirus infection [150]. In addition in longitudinal studies, which, together with a cluster of to pathogens, here we have argued that tumors, which are immune parameters designated the immune risk profile probably very common in the elderly but not clinically (IRP, see next section), constituted a super-additive risk of apparent in most, and which are immunogenic, are also mortality [138]. However, the efficacy of any approach to likely to contribute [104]. Therefore, strategies to reduce influence inflammation is very much open to question, as these sources of chronic antigenic stimulation could have inflammation also has protective effects against patho- a general immunorestorative role on age-associated gens. From a theoretical point of view, given clear associ- immune dysfunction. Page 10 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 The presence of cancer is commonly associated with com- enza virus vaccination produced higher antibody titres promised immune responses [95]; surgical removal of the and were better protected than controls vaccinated with- tumour can result in restoration of immunity [151]. By out IL-2 pre-treatment [159]. A more recent study using a analogy, reducing the antigenic load in the elderly, for novel IL-2-supplemented liposomal vaccine in 48 elderly example, by applying antiviral agents, might be beneficial people also found better responses with IL-2 [160]. It (although some of these agents may themselves be immu- remains extremely important to confirm and extend these nosuppressive [152]. Alternatively, the failure of the studies. immune system to entirely eliminate persistent herpesvi- rus infection may represent a trade-off with some actual The requirement for improved vaccination protocols benefits to the host; at least in mice (but only middle-aged applies not only to infectious disease but possibly also to were tested....), infection with a virus that is similar to vaccination against cancer, primarily a disease of the eld- human CMV seems to confer protection against infection erly, as illustrated by differences in responses to anticancer with certain bacteria [153]. The mechanism for this vaccinations in young and old mice [161]. Clearly, how- appears to be by maintaining a higher level of pro-inflam- ever, vaccination can only be effective if cells that are capa- matory mediators in the periphery, especially IFNγ; how- ble of responding are still present in the repertoire. These ever, this could be part of the problem, protective in the may be either naïve cells to be stimulated with vaccine young, but detrimental in the elderly. So, we may again be containing novel antigens, or memory cells requiring seeing a trade-off between pro-inflammatory status con- boosting by previously encountered antigen. For naïve ferring protection against infection in early life but anti- cells, as discussed above, the main question is whether old inflammatory status conferring an advantage in later life individuals still have any towards the end of their lives [154]. and if so, whether they are fully functional. In mice, naïve T cells from old animals do seem to be impaired [162]. Vaccination CD4 T cells show decreased helper activity and IL-2 pro- One of the greatest practical health-care challenges in the duction [163], which can nevertheless be partially elderly is to ensure that vaccinations are optimally effec- restored by exposure to a mixture of pro-inflammatory tive. Increasing the efficacy of influenza vaccination cytokines (IL-1, IL-6 and TNF) [164]. Thus, judicious local would have an enormous impact on health and well use of these cytokines as adjuvants might be beneficial. being, but other vaccinations, including those currently However, in elderly humans, there may be vanishingly under development for treating cancer [155] will also few naïve cells remaining that could be targeted in this become more important in this respect. Effective vaccina- way [165]. tion may not only protect against the specific pathogen, but also may result in enhanced activity of the NK-cell sys- Concluding remarks tem, which in turn may be associated with better specific If the elderly must mostly rely on their memory T cells for vaccine responses [119]. A combination of improved vac- pathogen and cancer control in later life, it becomes cru- cines with better adjuvants and immunostimulatory cial to know whether these are retained and function nor- agents would be of further benefit, as the commonly mally [166], and if not, what can be done about it. In applied adjuvant alum is only marginally effective in the mice, depletion of the dysfunctional naïve T cells can elderly [156] and in fact mostly enhances antibody result in their replacement by functional recent thymic responses, whereas resistance to viruses and cancer may emigrants [163]. This approach, coupled with thymic benefit more from enhanced cellular immunity [90]. regeneration and HSC maintenance, could have a marked clinical impact. Better understanding of immune dysfunc- There is great promise in using TLR ligands that strongly tion in human ageing will increase the probability of dis- enhance immunization efficacy and IL-2 production covering means to restore appropriate function and [157]. The putatively dysfunctional CMV-specific alleviate the burden of infectious disease and cancer late + - CD8 CD28 T cells that accumulate in the elderly and that in life, and may possibly also benefit younger cancer seem to be anergic and apoptosis-resistant directly ex vivo patients as well. Key questions remaining are the relative may be restored to functional competence by culturing importance of age-associated alterations in adaptive and them with IL-2. In this respect, they behave like anergic T innate immunity, especially NK activity, to human health cells in many experimental systems, in which alternative and longevity; the relative roles of CMV-vs-other persist- approaches including blocking inhibitory receptors, such ent infections, such as with parasites rather than viruses, as PD1 mentioned above, can restore T-cell function in sit- in accelerating immunosenescence and their impact on uations of chronic antigen exposure [158]. One option areas of immunity other than T cell immunity; whether could be therefore to treat the elderly with recombinant pathogen load and tumor antigen load act additively or, IL-2; an early study reported that 39 elderly people given worse, synergistically, in hastening immunosenescence well-tolerated low-dose IL-2 just before receiving influ- Page 11 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 14. Weksler ME, Goodhardt M, Szabo P: The effect of age on B cell and, obviously, how to intervene effectively to reconsti- development and humoral immunity. Springer Semin Immun- tute appropriate immune function throughout life. opathol 2002, 24:35-52. 15. Ogata K, An E, Shioi Y, Nakamura K, Luo S, Yokose N, Minami S, Dan K: Association between natural killer cell activity and infec- Competing interests tion in immunologically normal elderly people. Clin Exp Immu- The authors declare that they have no competing interests. nol 2001, 124:392-7. 16. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panour- gia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli Authors' contributions S: Inflammaging and anti-inflammaging: a systemic perspec- All authors contributed to drafting the manuscript. All tive on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007, 128:92-105. authors read and approved the final manuscript. 17. Kovaiou RD, Herndler-Brandstetter D, Grubeck-Loebenstein B: Age-related changes in immunity: implications for vaccina- Acknowledgements tion in the elderly. Expert Rev Mol Med 2007, 9:1-17. 18. Ouyang Q, Wagner WM, Wikby A, Walter S, Aubert G, Dodi AI, This position paper is based on presentations and discussions at the The Travers P, Pawelec G: Large numbers of dysfunctional CD8+ T European Conference on Cancer and Aging – SeneCa, senescence and can- lymphocytes bearing receptors for a single dominant CMV th th cer – which took place in Warsaw, Poland between 4 – 6 October, 2007, epitope in the very old. J Clin Immunol 2003, 23:247-57. supported by the European Commission (contract LSSM-CT-2006- 19. Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A: Human immunosenescence: is it infectious? Immunol 037312). For a summary of the main presentations at the conference, see Rev 2005, 205:257-68. Pawelec and Solana (2008)[167]. GP's laboratory was supported by the 20. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Deutsche Forschungsgemeinschaft (DFG PA 361/11-1; SFB 685 B04) and Nayak L, Moss PA: Cytomegalovirus seropositivity drives the the European Commission (QLK6-2002-02283, T-CIA; LSHC-CT-2004- CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 2002, 169:1984-92. 503306, ENACT; LSHG-CT-2007-036894, LifeSpan). RS was supported by 21. Looney RJ, Falsey A, Campbell D, Torres A, Kolassa J, Brower C, Ministerio de Sanidad y Consumo Instituto de Salud Carlos III – FEDER, McCann R, Menegus M, McCormick K, Frampton M, Hall W, Abra- grants FIS-PI061320 and Spanish Network for the Research in Infectious ham GN: Role of cytomegalovirus in the T cell changes seen Diseases (REIPI RD06/0008). in elderly individuals. Clin Immunol 1999, 90:213-9. 22. 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Publisher: Springer Journals
Copyright: Copyright © 2008 by Derhovanessian et al; licensee BioMed Central Ltd.
Subject: Biomedicine; Immunology; Geriatrics/Gerontology; Aging
eISSN: 1742-4933
DOI: 10.1186/1742-4933-5-11
pmid: 18816370
Publisher site: See Article on Publisher Site

Abstract

Compromised immunity contributes to the decreased ability of the elderly to control infectious disease and to their generally poor response to vaccination. It is controversial as to how far this phenomenon contributes to the well-known age-associated increase in the occurrence of many cancers in the elderly. However, should the immune system be important in controlling cancer, for which there is a great deal of evidence, it is logical to propose that dysfunctional immunity in the elderly would contribute to compromised immunosurveillance and increased cancer occurrence. The chronological age at which immunosenescence becomes clinically important is known to be influenced by many factors, including the pathogen load to which individuals are exposed throughout life. It is proposed here that the cancer antigen load may have a similar effect on "immune exhaustion" and that pathogen load and tumor load may act additively to accelerate immunosenescence. Understanding how and why immune responsiveness changes in humans as they age is essential for developing strategies to prevent or restore dysregulated immunity and assure healthy longevity, clearly possible only if cancer is avoided. Here, we provide an overview of the impact of age on human immune competence, emphasizing T-cell-dependent adaptive immunity, which is the most sensitive to ageing. This knowledge will pave the way for rational interventions to maintain or restore appropriate immune function not only in the elderly but also in the cancer patient. in animal models and is supported by epidemiological Introduction Cancer is largely a disease of older people; the median age evidence, such as increased frequency of certain cancer for cancer diagnosis in industrialised countries is types in immunosuppressed individuals [4,5]. Here, we approaching 70 years of age and is expected to increase discuss the effects of age on immune-cell development [1]. This can be due to different reasons, such as increased and function, as well as the dynamics and turnover of duration of carcinogenesis or the susceptibility of aging immune cells in the elderly, and speculate as to whether cells to environmental carcinogens [2,3]. Another mecha- many of these changes are the result of persistent chal- nism responsible might be reduced immune function, lenge by a range of antigen types including cancer anti- "immunosenescence", in the elderly. The importance of gens. Immune correlates with response to vaccination and the immune system in preventing tumor formation, mortality and possible interventions to restore appropri- termed immunosurveillance, has been repeatedly shown ate immunity and enhance responses to vaccination in the Page 1 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 elderly are also discussed. This will be of crucial impor- Studying immune cells directly ex vivo, as well as in culture tance not only for vaccination against common pathogens models of ageing in vitro, has contributed to our under- such as influenza [6], but for the increasing application of standing of age-associated changes in human T-cell-medi- immunotherapy for cancer in the elderly. Especially in the ated immunity. However, exactly which factors are most latter case, the mild or absent side effects of immuno- important in immunosenescence and what causes these therapy compared to chemotherapy of cancer may make age-associated changes remain largely unclear. Accumu- this approach particularly desirable in the frail older can- lating data initially unexpectedly implicated infection cer patient. with persistent herpesviruses, particularly cytomegalovi- rus (CMV), as contributing to the age-associated changes Impact of aging on immune parameters observed in many studies of human immune ageing [18- In elderly people, the ability to respond in a versatile way 22]. By analogy, long-term exposure to other persistent to pathogens, and potentially to cancer, is reduced due to stimulating agents, possibly parasite antigens rather than dysregulated immunity, a state known as immunosenes- CMV, especially in developing countries, as well as dysreg- cence. This is characterized firstly by low numbers of naïve ulated responses to autoantigens and cancer antigens, T cells in the peripheral blood [7] and probably also in may yield similar effects. Clearly, more detailed knowl- other immune organs such as the lymph node [8], which edge of the reasons for immune dysfunction at advanced is robustly observed in different human populations [9]. age and development of strategies to prevent or reverse There is a corresponding reduction in the diversity of the this should contribute to maximizing healthy lifespan for naïve T-cell receptor (TCR) repertoire, which helps to the ever-growing numbers of elderly people in industrial- explain the decreased ability of the elderly to resist infec- ized and, increasingly, in industrializing countries. tions to which they were not previously exposed, or to respond to the de novo appearance of tumor antigens. Sec- Immune-cell development ond, although the number of memory T cells increases, The cells of the immune system turn over rapidly, so com- there is a decrease in the diversity and functional integrity promised production or function of haematopoietic stem + + of both the CD4 and CD8 T-cell subsets [10,11] which cells (HSCs) would affect all aspects of immunity down- contributes to the decreased ability of the elderly to stream [23]. There is evidence for an association between respond adequately to re-infection or to retain memory HSC decline and longevity [24] probably due to differ- for cancer antigens expressed by relapsing tumors. Moreo- ences in DNA damage repair [25,26]. Purified HSCs from ver, the ability to respond appropriately to persisting old mice have less ability to reconstitute haematopoiesis infection or persistent exposure to other antigen sources, [27]. It has been recently suggested that the observed age- such as cancer antigens, may also be compromised, a associated skewing of hematopoiesis away from lym- process sometimes termed "immune exhaustion" [12]. phocyte generation may be one of the factors contributing to increased cancer occurrence with age [28]. There is also The focus of much research on immunosenescence has a gradual decline in the ability of mouse HSCs to progress been T cells, mainly because antigen presentation by den- through the various B-cell differentiation stages, partly dritic cells (DCs) generally seems well-retained in the eld- reflecting microenvironmental changes. These may erly [13], and because appropriate B cell [14] function involve altered production of interleukin-7 (IL-7) by stro- depends on helper T cells. This is not to imply that non- mal cells [29]. Changes at the level of T-cell progenitors clonotypic immunity is entirely resistant to age-related also contribute to age-associated deficits in mice [30]. In changes, or unimportant, but the alterations to natural any event, age is likely to impact both on HSCs and the killer (NK) cells and other innate immune cells [13] seem niche environment that determines their fate (Figure 1). to be less marked than those seen with T cells. Nonethe- less, it has been reported that NK cell status can predict Although even the very elderly can retain some degree of morbidity and mortality in the elderly, emphasizing the thymic function [31], thymic involution which represents importance of innate as well as adaptive immunity in the next hurdle that a T-cell progenitor must overcome in ensuring healthy longevity and possibly cancer resistance order to develop into a mature naïve T cell. That this could [15]. In addition, and at least partly because of innate be clinically important in cancer is demonstrated in a immune activity, the levels of pro-inflammatory factors study of age-dependent glioma-associated mortality, in are commonly increased in the elderly and are associated which the numbers of CD8 recent thymic emigrants with negative effects on health [16]. Together, these accounted for the effect of age on clinical outcome [32]. changes contribute to morbidity and mortality, and are However, assessing immune reconstitution after HSC associated with poor responses to vaccination against transplantation has demonstrated exceedingly low levels pathogens such as those causing influenza and pneumo- of thymic activity after the age of around 40 years [33]. nia [17], leading to decreased quality of life and increased Exactly why thymic involution occurs remains unclear. health-care burdens in later life. Because the most marked (but not the only [34] changes Page 2 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 Impa Figure 1 ct of ageing on immune cell development Impact of ageing on immune cell development. Genetic and environmental influences modulate age-associated altera- tions to the number and function of HSCs in the BM, resulting in skewed production of leukocytes. Reduced production of T cell progenitors, together with age-associated thymic involution, results in a relatively larger impact of age on T cells than on other leukocytes. to thymic size and structure occur around puberty, it has ences, with less peripheral blood [41] and follicular DCs been suggested that increased levels of sex hormones con- [42]. Chemotaxis and phagocytosis may be impaired in tribute to causing thymic involution; thymic output of DCs, as well as neutrophils [13], from the elderly [43]. naïve T cells can increase in both mice and humans fol- DCs from young and elderly people are reported to stim- lowing androgen ablation [35,36]. Nevertheless intrinsic ulate naïve CD8 T cells equally well, but those from the defects in the commitment of haematopoietic stem cells elderly may fail to stimulate naïve CD4 T cells properly to the lymphoid lineage [37] and the migration of T-cell [43], perhaps due to altered signal transduction pathways progenitors into the thymus have also been implicated in involving phosphoinositide 3-kinase signalling [44]. In this process [38]. Whatever the reason, it is clear that cancer, the effect of the tumor on the APC may enhance major age-associated changes to the thymus and greatly these deficits [45]. Many active immunotherapy protocols decreased output of naïve T cells are observed in both for cancer patients rely largely on DCs to be recruited to mice and humans (Figure 1). The elderly must therefore the site of vaccination and take up the vaccine antigen. increasingly rely on naïve T cells already previously pro- Reduced DC numbers as well as their chemotactic and duced and the small numbers possibly still being pro- phagocytic activity in the elderly might represent another duced. The presence of cancer, or particularly the hurdle to be overcome in developing successful vaccina- treatments applied as cancer therapy, are also likely to fur- tion strategies for elderly cancer patients. ther compromise any residual thymic function [39]. One very good example of the interplay between innate Innate-adaptive immune interactions and adaptive immunity is illustrated by γδ-T cells [46], In the next stage in T-cell-dependent immunity, naïve T which also show age-associated alterations. These are able cells must be activated by appropriate contact with anti- to recognize phosphoantigens present on cancer cells and gen-presenting cells (APCs), such as DCs (Figure 2). have anti-tumor activities, as well as other functions, such Although DCs seem to be only subtly different in the eld- as anti-CMV activity [47]. Their numbers rise from birth to erly in many respects [40], there are quantitative differ- puberty and gradually decrease again beyond 30 years of Page 3 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 A Figure 2 ge-associated changes to DCs Age-associated changes to DCs. Reduced numbers and functions of of DCs, together with reduced numbers of naïve T cells in the periphery of aged individuals further conspire to ensure that T cell function is depressed in the elderly due to the relative decrease in T helper cell activation. age, and they show functional alterations [48,49]. A func- varying proportions of the different T-cell subpopulations tional analysis in young/adult and middle aged donors in each individual, which cannot be assumed to manifest revealed that effector/memory γ9/δ2 CD27- T cells are identical age-related changes. increased after in vitro culture in the presence of specifi- cally stimulatory isopentenylpyrophosphate and IL-2 for There is no evidence for alterations to the actual structure 10 days. In contrast, this did not occur when using cells of TCRs or co-stimulatory receptors with age, but it is from old subjects, confirming a lack of naive and central likely that their assembly into functional units is compro- memory cells responding to IL-2 [50,51]. In these mised, leading to alterations in the assembly of the signa- respects, γδ T cells behave quite similarly to conventional losome (Table 1). One major factor that influences TCR αβ T cells, as discussed in the next section. assembly is cell membrane fluidity, as first suggested many years ago [52]. However, this changes according to T-cell function and ageing systemic fatty-acid availability, as illustrated by infusing Changes at the single-cell level lipids into young volunteers [53], and not necessarily as a To mediate an adaptive immune response, T cells must result of ageing. Nonetheless, the increased levels of cho- interact with functional APCs, become activated and lesterol which occur commonly in the elderly might well undergo extensive clonal expansion, followed by clonal contribute to age-associated deficits in T-cell signalling contraction. Alterations in either the number or the struc- [54]. High cholesterol levels are also found in some can- ture of cell-surface receptors, as well as their location in cers, at least before the metabolic dysregulation caused by the membrane, and, once assembled, their intracellular the tumor results in their lowering as the disease signalling pathways, could all contribute to the final out- progresses (see, for example, [55,56]). come of each T-cell-DC interaction. Studies have focused on alterations in signal transduction as well the formation Although the number of TCR molecules per T cell does of signalling domains (such as the immunological syn- not seem to change with age [57], there are clear altera- apse). The interpretation of much of the published data is, tions in the number and balance of receptors that mediate however, complicated by the use of samples consisting of positive or negative co-stimulatory signals. Decreased or Page 4 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 absent expression of the most studied of these cell-surface cells, are not well documented. For example, the well- molecules, CD28, is commonly referred to as a biomarker known age-associated decrease in activation of the SRC- for immunosenescence [58], because highly differentiated family protein tyrosine kinase LCK, which is one of the - + CD28 T cells, especially within the CD8 T-cell subset, earliest events after TCR ligation and thought to be essen- tend to accumulate in the peripheral blood of the elderly tial for T-cell stimulation, was recently shown to be crucial and because CD28 expression is lost after extended cul- only for naïve T cells (at least in mouse CD8 T cells) [65], ture in vitro as T cells undergo differentiation and enter a of which the elderly simply possess fewer. state of replicative senescence [58]. Studies of cultured T cells have confirmed that decreases in CD28 expression Changes at the cell population level do occur within monoclonal populations as they undergo Naïve T cells express CC-chemokine receptor 7 (CCR7) clonal expansion and progress through their finite and leucocyte common antigen isoform CD45RA [66] lifespan, excluding the possibility that a small population and have long telomeres [67], whereas many memory T - + of originally CD28 cells overgrows the CD28 cells [59]. cells express the alternative splice variant CD45RO, have Nonetheless, the definition of such changes as biomarkers lost CCR7 and have shorter telomeres [68] suggesting an of immunosenescence remains problematic, because, for extensive proliferative history due to lack of telomere example, CD28 is downregulated by tumour-necrosis fac- maintenance. The advent of polychromatic flow cytome- tor (TNF) [60] and upregulated by IL-12 [61], not neces- try is facilitating the ever-finer ex vivo dissection of differ- sarily associated with senescence. It has also been difficult ent T-cell subpopulations and the changes in their to establish whether the much-investigated altered signal proportions with age. The best biomarker of immune age- transduction pathways in T cells are a result of an altered ing remains the relative levels of naïve T cells (defined as + + + + + balance of expression of positive and negative co-stimula- CD45RA CD27 CD28 CD62L CCR7 ) and memory cells tory receptors [62,63], determining the final outcome – (with a wide range of other phenotypes [69] and which activation, anergy or apoptosis of the T cell. Further stud- also exhibit age-related differences in TCR diversity, tel- ies on clonal populations in culture should facilitate dis- omere lengths and various other factors). To mount an tinguishing between changes caused by altered adequate response, a broad TCR repertoire must be main- proportions of cell subsets and changes within the same tained by ensuring the continuing presence of a diverse clones at different times; a first global gene expression population of T-cell clones, but this decreases with age. At analysis of early and late passage T-cell clones has revealed least for CD4 T cells, this may occur quite suddenly, with a wide range of differentially expressed genes, including TCR diversity well maintained up to the age range of those encoding proteins involved in signal transduction 60–65 years, despite the marked decrease of thymic out- and apoptosis [64]. Regarding TCR signalling in young put. However, repertoire diversity in 75–80 year olds is and old T cells, even here, the differences between naïve severely reduced [10] and probably contributes to the + + and memory T cells, as well as between CD4 and CD8 T poor responses to infection and vaccination in this age Table 1: Impact of age-associated signalling changes Features altered Resulting altered mechanism Cholesterol level Signalling molecule recruitment [135] Membrane fluidity Protein interaction [54] Lipid raft functions Early signalling/immune synapse formation [135] Calcium influx Induction of T cell activation Phosphatase activity Control of negative signalling PTK (Lck) activity Phosphorylation of LAT [57,135] LAT phosphorylation Activation of LAT-associated molecules MAP Kinase activation Cellular activation/survival [57,135] Cytoskeleton rearrangement Cell-cell contact/Immune synapse formation Translocation of transcription factors Induction of gene expression CD28 expression T cell costimulation/anti-apoptotic signals [58] KIR expression Formation of an activation platform KLRG-1, CD57, PD-1 expression Induction of T cell activation [92,158] For activation, T cells require sustained physical contact with APC. This feature is altered with age due to changes in the integrity of the membrane. Several signalling molecules fail to be activated with age, including PTK and adaptor proteins such as LAT. Calcium metabolism is altered, partly due to impaired PLCγ-1 phosphorylation. The alterations including lipid raft functions influence MAP Kinase activation and cytoskeletal rearrangements, together leading to differential activation and translocation of transcription factors such as NF-κB, NF-AT and AP-1 into the nucleus. This directly affects T cell clonal expansion due to decreased IL-2 production. Unbalanced negative signalling involving inhibitory receptors such as KIR2DL2 or Natural Killer Receptors contribute to reduce activation. PTK: protein tyrosine kinase; LAT: linker for activation of T cells; MAPK: Mitogen activated protein kinase; KIR: inhibitory killer immunoglobulin-like receptors; PLCγ-1: Phospholipase C-gamma 1. Page 5 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 group (Figure 3). The likely clinical implications of this cell subsets were proliferating and whether the rate of are reflected in the close correlation between the diversity expansion was different in people of different ages. Pio- neering work in which deuterated glucose is incorporated of the repertoire and remaining survival time in very old people [11]. One explanation for these events could be into dividing lymphocytes to distinguish the fraction of that because T cells are maintained in a state of constant the pool that proliferates during the labelling time is tech- turnover in the body, which is either antigen driven or nically challenging but very informative in humans and homeostatic, replicative senescence (proliferative exhaus- has now been applied to T cells, B cells and NK cells. In tion) occurs [70]. In cell culture, CD4 T cells become naïve, memory and regulatory T-cell subsets, label uptake more susceptible to apoptosis at this time of proliferative and loss occurs rapidly but at different rates in each sub- exhaustion [71], whereas CD8 T cells become apoptosis set, thus indicating divergent rates of cell division, with resistant [72]. The implication of these results is that in regulatory T cells proliferating most rapidly [74]. How- + + vivo, CD8 T cells would accumulate and CD4 T cells ever, the only substantial difference between young and + + + would be lost by clonal deletion, and the CD4 :CD8 T- old donors is that the CD8 memory T cells have a much cell ratio would therefore change. There is indeed evi- longer half-life than any other subset in the elderly, but T cells in vivo, and for dence for the accumulation of CD8 not in the young [75]. These results are consistent with an their correlation with poor outcomes to vaccination and accumulation of CD8 T memory cells in the elderly. In B with mortality, as discussed in more detail below. cells, there are also only slight differences between young and old individuals, with memory B cells turning over Immune cell dynamics and turnover more rapidly than naïve B cells [76], whereas in NK cells, Despite decreased thymic output of T cells, in healthy peo- the production and proliferation rates were lower in the ple, the overall number of T cells in the periphery remains elderly than in the young [77]. Nonetheless, B cell mem- remarkably constant at different ages, although there may ory may be maintained for a very long time; thus, it has be an association between slightly lower levels of both been recently shown that individuals who survived the + + CD4 and CD8 cells and mortality at 10-year follow-up Spanish flu (H1N1) still have specific antibodies 90 years [73]. Until recently it was impossible to determine which after the epidemic. These donors still possess circulating B cells that secrete antibodies that binding the respective recombinant haemagglutinin protein [78]. Given the high measured levels of peripheral T-cell turno- ver, it is not surprising that their proliferative potential eventually becomes exhausted; these exhausted cells are characterized by a lack of CD27, CD28 and telomerase expression [79], and by having short telomeres [80]. Memory T-cell turnover may not only result in an eventual loss of the cells, but also in an active acquisition of sup- pressive activity as demonstrated in vitro [81] and more recently in vivo, suggesting that development of regulatory T cells (Tregs) from terminally-differentiated CD4 cells can take place [74]. Tumor antigens as the driving force in this process might account for the commonly-observed H th Figure 3 y e h pot uh man lifespan etical model for the evolution of T cell immunity over higher levels of Tregs in cancer patients, which are Hypothetical model for the evolution of T cell immu- believed to be a bad prognostic sign, and to interfere with nity over the human lifespan. Age-associated changes to immunotherapy [82]. Mechanisms therefor may include T cell immunity result in decreasing proportions of naïve cells competition for antigen on the DC surface, or altered and increasing proportions of memory cells over the lifespan. TCR repertoire diversity is well-maintained at least until the cytokine secretion patterns [59]. At least for pathogens end of the reproductive period, when repertoire shrinkage establishing only acute infection, antigen seems not to be occurs rapidly. This point is reached as the number of differ- required for the constant turnover of specific memory T ent clonal expansions caused by persistent pathogens, as cells. In mice after clearance of acute viral infection, mem- demonstrated for CMV, plateaus and then decreases. Loss of ory T cells persist for the lifetime of the animal and also repertoire diversity in memory cells is not paralleled by their undergo clonal expansions and accumulate even in the decreased numbers; on the contrary, these continue to rise absence of the original antigen [83]. Thus, T-cell clonal as dysfunctional cells accumulate, possibly a compensatory exhaustion may be an intrinsic characteristic of adaptive mechanism. At this time also, responses to vaccination, as immunity, which still occurs even in the absence of documented with influenza vaccination, are much less effec- chronic infection [84]. However, the biological norm is tive than at earlier time points. likely to be chronic infection; in humans, mostly herpes Page 6 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 viruses, especially CMV and in CMV-negative elderly indi- The apoptosis-resistant cells that accumulate in both old viduals, Epstein-Barr virus (EBV), may be the main agents mice and humans may be dysfunctional in several ways. T cells to exhaustion [85]. In different envi- driving CD8 In young mice, the number of T cells staining with soluble ronments, possibly where EBV and CMV are not so preva- MHC/peptide multimers loaded with influenza-virus lent, other pathogens may play a similar role. Analogous epitopes is very similar to the number of T cells producing phenomena of clonal exhaustion and senescence may interferon-γ (IFNγ) on antigen stimulation, indicating also occur in HIV disease [86] and autoimmunity [87,88], that essentially every antigen-specific cell present is able to and, as we argue here, cancer. Although the proliferative respond to antigen. However, in old mice, the number of reserve of T cells is high, at least until telomere erosion tetramer-positive cells exceeds the number of IFNγ-pro- reaches its critical limit (termed the Hayflick limit), being ducers, indicating that a proportion of the antigen-specific approximately 70 population doublings for CD4 T cells cells fails to respond. This is quite similar to the situation [70], the old idea that T-cell clonal exhaustion leads to in very elderly individuals who accumulate large clonal clonal attrition and has clinical consequences has stood expansions of CMV-specific T cells, the majority of which the test of time. The clinical consequences may be broad are dysfunctional (or anergic). Longitudinal studies of and impact not only on those very advanced in years, as elderly Swedes have established that individuals with the discussed in the next section. largest accumulations of clonally expanded CD8 T cells, most of which are CMV-specific and have a mature phe- - - + + Immune biomarker correlates with response to vaccination notype (CD27 CD28 CD57 KLRG1 ) [92,93], have a and mortality shorter remaining survival time than people of the same Establishing reliable biomarkers identifying T-cell subsets age with less of these cells at baseline. In CMV-positive and determining which are the most relevant to healthy subjects, the number of different clonal T-cell expansions ageing and adequate responses to vaccination requires increases from middle age to old age and decreases in the longitudinal studies following the same individuals over terminal phase of life, resulting in a highly significant cor- time and correlating test parameters with clinical outcome relation between the number of T-cell clones and survival (such as mortality, pathology and vaccination responses). of the individual [11]. This finding suggests that eventual Cross-sectional studies have the disadvantage that the loss of control of CMV infection after a lifetime of immu- young and old populations compared will have differed nosurveillance may indeed be a cause of mortality in this tremendously in their previous exposure to environmen- elderly population (Figure 4). Whether this will be a gen- tal factors of all kinds, and probably, also genetic consti- eral finding in other populations remains to be seen. tution. However, so far, most human studies have been Clonal expansions of CD8 T cells are also found in old cross-sectional, and because of logistical constraints we mice; whether this is antigen independent (random TCR cannot even be sure whether acute infectious complica- usage; homeostatic proliferation) or antigen driven may tions are really more severe in the elderly due to impaired depend on the pathogen environment [94]. Thus, innate and adaptive immunity or due to other factors. although antigen driven, especially CMV-stimulated, T- Apparently simple questions such as the correlation of cell clones may be the type most frequently found in aged immune status with outcome of vaccination in the elderly humans, this finding suggests that there are multiple, cannot yet be answered definitively. Correlations between independent mechanisms that can contribute to age- the presence of certain T-cell subpopulations and poor altered CD8 T-cell homeostasis. All these findings suggest that dysfunctional, end-stage differentiated cells may responses to vaccination against influenza virus have, + - however, been reported. Excessive CD8 CD28 T cells cor- accumulate in various physiological situations [95]. To relate with poor responsiveness, whereas, counter-intui- what extent this process is amplified in CMV carriers who + + tively, frequencies of CD4 memory T cells, regardless of are also cancer patients, and not only for CD8 but also CD28 expression, do not [89]. In mouse models, the virus CD4 T cells as well as possibly components of innate is cleared from the lungs more slowly in old than young immunity [13,96] must be further investigated. This mice, correlating with a delayed and decreased peak of notion is consistent with the hypothesis that such CD8 cytotoxic T-cell production. Thus, cellular responses are cells fill the "immunological space", thereby decreasing crucial for controlling the virus but do not function ade- immune competence and raising the possibility of inter- quately in old animals; this appears to be likely in humans vening to restore appropriate immunological function too [90]. In mice, cell transfer experiments demonstrated [97,98]. As we learn more about the dysfunctional status that it was both the old environment and the old cells that of these cells, in terms of basic biochemical functions contributed to the problem – that is, even young func- [99,100] and receptor signalling [101] we may begin to tional T cells do not respond properly when transferred to identify biomarkers that can be used in monitoring ther- an old environment (and neither do old T cells when apy success [102,103]. There is some evidence for the transferred to a young environment) [91]. existence of such "exhausted" cells in cancer patients [104,105]. Whether the accumulation of dysfunctional Page 7 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 Decreasing Figure 4 regenerative reserve in immunosenescence Decreasing regenerative reserve in immunosenescence. Hypothesis: In the elderly, dysfunctional, often CD8+ CMV- specific T cells accumulate because apoptotic pathways are compromised. Vital memory cells are eventually lost by clonal attri- tion (clonal exhaustion). Loss of memory cells for previously encountered pathogens contributes to morbidity and mortality. Thus, decreased clonal heterogeneity correlates with mortality in longitudinal studies. Because T cell homeostasis maintains constant numbers of T cells in the periphery, even the age-associated decreased thymic-output of naive cells is blocked, and the shrink- age of the naive T cell repertoire contributes to increased susceptibility to newly-encountered infectious diseases. IM, infec- tious mononucleosis; PD, population doublings. cells can influence response to therapy, in particular to ceptible to deleterious changes with age, but innate immunotherapy in cancer patients, remains to be responses tend to be better-preserved [108]. In fact, reten- explored; very few approaches to this question have been tion of strong inflammatory responses with age, but now made so far, but a limited literature exists in animal mod- in the absence of the counterbalancing and beneficial els. effects of the adaptive responses that they normally amplify at younger age may even enhance immunopa- Cancer immunity and ageing thology and carcinogenesis. This might also help to The extent to which tumors are controlled by immunity is explain the genetic component of certain cancers in which controversial. Nonetheless, there is clear evidence for the inflammation is well-established as an amplificatory fac- immunogenicity of cancer cells and large numbers of can- tor [109]. On the other hand, tumors may be less aggres- cer immunotherapy trials have shown beyond reasonable sive in the elderly, as seen in breast, lung, colon and other doubt that T cells recognizing tumor antigens can be sites in very old people and centenarians, partly because amplified in many patients. The calculated frequency of of the lower inflammatory status of "successfully aged" cells responding to a vaccine antigen (MAGE-3) in people, which also decreases the ability of the stromal tis- melanoma suggests that responding T cells must divide a sue to support tumour growth and angiogenesis [110]. large number of times to generate the observed number of responding cells and to be effective in patients [106]. This According to these considerations, young and old individ- extreme requirement for clonal expansion might well be uals will most likely require different treatment partially responsible for the lack of success of many cancer approaches, which could solve some of the problems of vaccination trials, due to the phenomenon of replicative treating geriatric cancer patients with other, more tradi- senescence in T cells [70]. tional, modalities. Cancer could be less responsive to chemo- and radiotherapy in the elderly, and this might be Limited studies in preclinical animal models have indi- because the immune system is less effective in the elderly, cated age-associated alterations in tumor immunity and following the notion that even responses to chemo- and therapeutic responses. Thus, in a mouse breast cancer radiotherapy require an intact immune system [111]. In model, there are effective anti-cancer immune responses the few animal models investigated thus far, cancer in young animals which are mostly mediated by T cells, immunity successful in young individuals is mostly less whereas the (less effective) responses in old animals pri- effective in older ones. Young mice injected with highly marily rely on innate immunity [107]. This could be a immunogenic tumors such as chemical- or radiation- general finding, because adaptive immunity is highly sus- induced sarcomas controlled the tumor better compared Page 8 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 to old mice. In contrast, tumors with weak immunogenic- BCR repertoire diversity due to clonal deletions, decreased ity, like B16 melanoma, were more aggressive and grew thymic and bone marrow output, and accumulations of better in young animals compared to old (reviewed in dysfunctional cells. In addition to avoiding over-eating [112]). Sometimes, decreased efficacy in old mice can be and ensuring that sufficient exercise is taken, what else can compensated for by increasing costimulation [113,114], be done to reconstitute immunity at old age? which is focussing efforts on improving adjuvants for the Restoring naive T-cell number and function purpose of better vaccination results in the elderly in gen- eral. This may be particularly important given the possible Given the paucity of naïve T cells in the elderly, enhance- synergistic effects of ageing and cancer on DC function, ment of thymic output is likely to be a first requirement such that the relative contribution of DC dysfunction may for maintaining or restoring their effective immunity. be greater in cancer than in healthy ageing [115]. How- However, although in a contrived experimental situation ever, as with other aspects of the complex interactions in mice, neonatal thymi grafted under the kidney capsule between cancer and ageing, it will be difficult to generalize exported the same numbers of T cells regardless of from one system to another. Thus, it has already been whether the peripheral pool was oversupplied (by thymic demonstrated that some immunotherapies are actually grafts) or undersupplied (due to neonatal thymectomy) effective only in old but not young animals [116], imply- [121], feedback mechanisms maintaining T-cell homeos- ing that patient-individualized therapies will have to take tasis in humans would be expected to prevent any residual the immunological age of the individual closely into thymic output due to the accumulated dysfunctional account. For this, it will clearly be necessary to differenti- CD8 T cells present in the periphery. This may be consist- ate between chronological age and the "functional" age of ent with age-associated decreases in thymic output of + + immunity, as could be based on the constellations of CD8 T cells being more marked than CD4 T cells, at least immune markers making up the "immune risk profile" or in mice [122]. Such CD8 T-cell accumulations could be the modified set of markers investigated by Hirokawa et reduced or eliminated by identifying ways of specifically al. mentioned above [105]. targeting the dysfunctional subset [98]. Efforts directed at thymic reconstitution could then follow. Possible interventions and improved vaccination strategies As discussed above, immunosenescence results from mul- In mice, it was reported that transplantation of aged invo- tifactorial processes that act on all components of the luted thymi into juvenile recipients led to reconstitution immune system and some approaches to reconstitute of the structure and function of the thymus [123]. Moreo- appropriate function have already been mentioned. ver, transplantation of cultured thymic fragments to Recent results from studies on long-lived non-human pri- patients with DiGeorge syndrome who lack a functional mates maintained on a calorie-reduced diet showing thymus, has been carried out successfully [124] and may improved maintenance and/or production of naïve T also be a conceivable approach to restore naive T-cell cells, better T-cell function and reduced pro-inflammatory numbers in the elderly. The use of T-cell survival factors, status [117], and the possible beneficial effects of moder- such as IL-7, has been explored in mice and monkeys, and ate exercise [118], serve to emphasize the continued rele- local delivery of this cytokine to the thymus by implanta- vance of common-sense medical advice in "anti-ageing" tion of genetically engineered stromal cells secreting it medicine as applied to immunosenescence. Although as may be a way of avoiding systemic effects [125]. Sex ster- ageing proceeds, the T- and to some extent B-cell compart- oid ablation in men undergoing therapy for prostate can- ments seem to be particularly susceptible to senescence, cer is reported to result in increased numbers of NK cells and other components of innate immunity are circulating naïve T cells, but this approach is obviously also affected. As mentioned above, some limited data do not generally applicable to the majority of elderly people point to a crucial impact of NK-cell status on resistance to [35]. More recently, other factors such as keratinocyte infectious disease and hence healthy longevity [15], as growth factor have been shown to improve thymic output well as being implicated in the outcome of influenza vac- in old mice [126]. Thymic epithelial cells, which are cination [119]. It is likely that NK cells also play a role in required to support thymocyte maturation, undergo determining the outcome of cancer immunotherapy apoptotic death in the aged thymus, through a pathway [103]. Clearly, it is not only the T-cell status and/or CMV involving interactions between FAS and FAS ligand. status of elderly subjects that affects the outcome of vacci- Because age-associated thymic involution is reported not nation [120], but also the pre- (and post-) vaccination to occur in aged FAS-deficient mice [127], blocking this NK-cell status [119] (although how much the latter is pathway locally in the thymus might also contribute to affected by CMV is not yet clear). It is therefore imperative retaining thymic functionality. The same may apply to that these studies are extended and repeated in different transforming growth factor-β2 (TGFβ2), as greater thymic populations. Nonetheless, the most severe clinical impact cellularity and higher levels of naive T cells are seen in old is likely to remain primarily the result of loss of TCR and TGFβ2-deficient mice compared to old wild-type mice Page 9 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 [128]. T cells that have undergone clonal exhaustion after ations of IL-6, for example, with frailty [139], reducing the chronic viral infection also express the B7-family receptor levels of such mediators would nonetheless be beneficial named programmed cell death-1 (PD1), that inhibits co- not only for improving immune status, via improved anti- stimulatory signals [129]. It has been suggested that gen presentation [140], for example, but also by its effect blocking PD1-mediated signalling could lead to on many other organ systems. Given the contribution of improved T-cell function [130]. inflammation to carcinogenesis, there may well be benefit of using anti-inflammatories in this context as well. Nutri- It is too early to say whether any of these approaches can tional intervention by caloric restriction, that was shown be translated to human therapy. It is possible that, among to improve the immune response in rodents [141], has its other effects, CMV has a role in reducing thymic out- also been shown to delay T cell immunosenescence in put: at least in clinical human HSC transplantation, out- non human primates, preserving the number and func- put of naïve T cells is reduced by CMV infection [131]. tion of naive T cells [117]. Steps taken to reduce CMV infection might therefore also benefit naïve T-cell production. Antigenic load Given the initially quite unexpected impact of infection Nutrition and inflammation with persistent herpesviruses on immunity in the elderly Interventions in nutrition, which are relatively easy to [19] strategies to reduce the infectious antigenic load carry out, could have a larger impact on immune function would seem to offer a reasonable approach to restoring than commonly appreciated, even in donors selected for appropriate immunity. The Swedish OCTO/NONA longi- very good health [132]. Vitamin E supplementation has tudinal studies [142] have revealed several changes in received much attention, and was recently reported to immune parameters predicting mortality at 2, 4 and 6 year reconstitute immunological synapse formation, especially follow-up, and summarized in what we have designated in CD4 naïve T cells of old mice [133]. However, many the IRP [143]. This is a cluster of immune biomarkers nutritional interventions could be viewed more as correct- which may be informative in several elderly populations ing poor diet, or reducing an inappropriately rich diet, but [144,145], as well as in other circumstances, for example, this alone could have a major impact on immunity in the for the occurrence of infections after HSC transplantation elderly. Given the notion that increased basal levels of [146] and autoimmunity [88]. An initially surprising find- inflammation and frailty in the elderly are intimately ing was the association of the IRP in the elderly with CMV related, anti-inflammatory nutritional interventions infection [147], but not with morbidity [148], which is could be useful [16]. Modulating lipid intake would be a consistent with the effect of persistent herpesvirus infec- possibility in this context, using, for example, conjugated tions on immunity. A recent study [149] has also shown a linoleic acid, which can result in decreased pro-inflamma- progressive accumulation of HSV-specific T cells with a tory cytokine secretion and which can increase the success central memory phenotype in old mice. However the con- rates of hepatitis B vaccination in the elderly [134]. As dis- tinuous administration of antiviral drugs did not alter the cussed above, the lipid environment strongly influences course of this accumulation of T cells. These results sug- T-cell function, and alterations in membrane fluidity gest the possibility that, at least in this experimental affect lipid raft and immunological synapse formation model, T cells expansions arise as a consequence of age- [52,135]. Human high-density lipoprotein extracts accu- associated homeostatic disturbances rather than repeated mulated cholesterol from lipid rafts, resulting in increased antigenic stimulation. Nevertheless, the direct influence TCR signal transduction and T-cell activation [136]. of CMV and other herpes viruses as a major driving force in T cell immunosenescence cannot be excluded. Thus, Use of non-dietary anti-inflammatory agents to decrease interventions targeting these viruses or the accumulated levels of IL-6, TNF and IL-1 may also assist in rebalancing dysfunctional memory cells specific for them [92], may be immunity; to this end, it might be possible to use rela- of clinical benefit both directly against viral infection and tively innocuous agents, such as statins, that are already in terms of improving responses to vaccination. The same being used extensively in the elderly to treat autoimmu- principle may apply to other human populations in areas nity and other diseases [137]. In particular, the level of IL- of differing pathogen load, for example parasitic infec- 6 was found to be an independent predictor of mortality tion, rather than herpesvirus infection [150]. In addition in longitudinal studies, which, together with a cluster of to pathogens, here we have argued that tumors, which are immune parameters designated the immune risk profile probably very common in the elderly but not clinically (IRP, see next section), constituted a super-additive risk of apparent in most, and which are immunogenic, are also mortality [138]. However, the efficacy of any approach to likely to contribute [104]. Therefore, strategies to reduce influence inflammation is very much open to question, as these sources of chronic antigenic stimulation could have inflammation also has protective effects against patho- a general immunorestorative role on age-associated gens. From a theoretical point of view, given clear associ- immune dysfunction. Page 10 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 The presence of cancer is commonly associated with com- enza virus vaccination produced higher antibody titres promised immune responses [95]; surgical removal of the and were better protected than controls vaccinated with- tumour can result in restoration of immunity [151]. By out IL-2 pre-treatment [159]. A more recent study using a analogy, reducing the antigenic load in the elderly, for novel IL-2-supplemented liposomal vaccine in 48 elderly example, by applying antiviral agents, might be beneficial people also found better responses with IL-2 [160]. It (although some of these agents may themselves be immu- remains extremely important to confirm and extend these nosuppressive [152]. Alternatively, the failure of the studies. immune system to entirely eliminate persistent herpesvi- rus infection may represent a trade-off with some actual The requirement for improved vaccination protocols benefits to the host; at least in mice (but only middle-aged applies not only to infectious disease but possibly also to were tested....), infection with a virus that is similar to vaccination against cancer, primarily a disease of the eld- human CMV seems to confer protection against infection erly, as illustrated by differences in responses to anticancer with certain bacteria [153]. The mechanism for this vaccinations in young and old mice [161]. Clearly, how- appears to be by maintaining a higher level of pro-inflam- ever, vaccination can only be effective if cells that are capa- matory mediators in the periphery, especially IFNγ; how- ble of responding are still present in the repertoire. These ever, this could be part of the problem, protective in the may be either naïve cells to be stimulated with vaccine young, but detrimental in the elderly. So, we may again be containing novel antigens, or memory cells requiring seeing a trade-off between pro-inflammatory status con- boosting by previously encountered antigen. For naïve ferring protection against infection in early life but anti- cells, as discussed above, the main question is whether old inflammatory status conferring an advantage in later life individuals still have any towards the end of their lives [154]. and if so, whether they are fully functional. In mice, naïve T cells from old animals do seem to be impaired [162]. Vaccination CD4 T cells show decreased helper activity and IL-2 pro- One of the greatest practical health-care challenges in the duction [163], which can nevertheless be partially elderly is to ensure that vaccinations are optimally effec- restored by exposure to a mixture of pro-inflammatory tive. Increasing the efficacy of influenza vaccination cytokines (IL-1, IL-6 and TNF) [164]. Thus, judicious local would have an enormous impact on health and well use of these cytokines as adjuvants might be beneficial. being, but other vaccinations, including those currently However, in elderly humans, there may be vanishingly under development for treating cancer [155] will also few naïve cells remaining that could be targeted in this become more important in this respect. Effective vaccina- way [165]. tion may not only protect against the specific pathogen, but also may result in enhanced activity of the NK-cell sys- Concluding remarks tem, which in turn may be associated with better specific If the elderly must mostly rely on their memory T cells for vaccine responses [119]. A combination of improved vac- pathogen and cancer control in later life, it becomes cru- cines with better adjuvants and immunostimulatory cial to know whether these are retained and function nor- agents would be of further benefit, as the commonly mally [166], and if not, what can be done about it. In applied adjuvant alum is only marginally effective in the mice, depletion of the dysfunctional naïve T cells can elderly [156] and in fact mostly enhances antibody result in their replacement by functional recent thymic responses, whereas resistance to viruses and cancer may emigrants [163]. This approach, coupled with thymic benefit more from enhanced cellular immunity [90]. regeneration and HSC maintenance, could have a marked clinical impact. Better understanding of immune dysfunc- There is great promise in using TLR ligands that strongly tion in human ageing will increase the probability of dis- enhance immunization efficacy and IL-2 production covering means to restore appropriate function and [157]. The putatively dysfunctional CMV-specific alleviate the burden of infectious disease and cancer late + - CD8 CD28 T cells that accumulate in the elderly and that in life, and may possibly also benefit younger cancer seem to be anergic and apoptosis-resistant directly ex vivo patients as well. Key questions remaining are the relative may be restored to functional competence by culturing importance of age-associated alterations in adaptive and them with IL-2. In this respect, they behave like anergic T innate immunity, especially NK activity, to human health cells in many experimental systems, in which alternative and longevity; the relative roles of CMV-vs-other persist- approaches including blocking inhibitory receptors, such ent infections, such as with parasites rather than viruses, as PD1 mentioned above, can restore T-cell function in sit- in accelerating immunosenescence and their impact on uations of chronic antigen exposure [158]. One option areas of immunity other than T cell immunity; whether could be therefore to treat the elderly with recombinant pathogen load and tumor antigen load act additively or, IL-2; an early study reported that 39 elderly people given worse, synergistically, in hastening immunosenescence well-tolerated low-dose IL-2 just before receiving influ- Page 11 of 16 (page number not for citation purposes) Immunity & Ageing 2008, 5:11 http://www.immunityageing.com/content/5/1/11 14. Weksler ME, Goodhardt M, Szabo P: The effect of age on B cell and, obviously, how to intervene effectively to reconsti- development and humoral immunity. Springer Semin Immun- tute appropriate immune function throughout life. opathol 2002, 24:35-52. 15. Ogata K, An E, Shioi Y, Nakamura K, Luo S, Yokose N, Minami S, Dan K: Association between natural killer cell activity and infec- Competing interests tion in immunologically normal elderly people. Clin Exp Immu- The authors declare that they have no competing interests. nol 2001, 124:392-7. 16. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panour- gia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli Authors' contributions S: Inflammaging and anti-inflammaging: a systemic perspec- All authors contributed to drafting the manuscript. All tive on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007, 128:92-105. authors read and approved the final manuscript. 17. Kovaiou RD, Herndler-Brandstetter D, Grubeck-Loebenstein B: Age-related changes in immunity: implications for vaccina- Acknowledgements tion in the elderly. Expert Rev Mol Med 2007, 9:1-17. 18. Ouyang Q, Wagner WM, Wikby A, Walter S, Aubert G, Dodi AI, This position paper is based on presentations and discussions at the The Travers P, Pawelec G: Large numbers of dysfunctional CD8+ T European Conference on Cancer and Aging – SeneCa, senescence and can- lymphocytes bearing receptors for a single dominant CMV th th cer – which took place in Warsaw, Poland between 4 – 6 October, 2007, epitope in the very old. J Clin Immunol 2003, 23:247-57. supported by the European Commission (contract LSSM-CT-2006- 19. Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A: Human immunosenescence: is it infectious? Immunol 037312). For a summary of the main presentations at the conference, see Rev 2005, 205:257-68. Pawelec and Solana (2008)[167]. GP's laboratory was supported by the 20. 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Pawelec G, Solana R: Are cancer and ageing different sides of the same coin? Conference on Cancer and Ageing. EMBO Rep 2008, 9:234-8. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 16 of 16 (page number not for citation purposes)

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