TY - JOUR
AB - PP-072-09 The theoretical study of different T cell responses K. Saeki K. Saeki Department of Biology, Kyushu University, Fukuoka, Japan Abstract Self-reactive naive T cells are mostly eliminated by the negative selection in the thymus, but this process is not perfect and some of them exist in the periphery. These autoreactive T cells are prevented from being activated by T cell anergy, regulatory T cells or other mechanisms. To induce the T cell anergy, the absence of costimulation has an important role. In the presence of the costimulation, however, the insufficient stimulation to T cell receptors can induce anergy, which is due to altered peptide ligands (Sloan-Lancaster et al. 1994) or low numbers of agonist ligands on antigen presenting cells (Korb et al. 1999). We suggest that these phenomena are explained by the idea that T cells estimate whether they are self-reactive or non-self-reactive by using the strength of the stimulation. If a T cell observes a strong stimulation, it should be activated because T cells which can be strongly stimulated by self-peptide is mostly eliminated by the negative selection. In contrast, if a T cell observes a weak stimulation, the probability that the T cell is self-reactive is higher than when it observes a strong stimulation. Then, anergy may be induced to suppress self-reactive T cells. In this research, we calculate the optimal T cell response when a T cell observes certain stimulation by a mathematical model, and show the dependence of the optimal response on the parameters (e.g. the frequency of self-reactive T cells). PP-072-10 Tolerance of CD8+ T cells in mice transgenic for a model antigen specifically expressed in muscle involves peripheral deletion E. Franck E. Franck 1 Inserm U905, Institute for Biomedical Research, University of Rouen, Rouen, France A. Salvetti A. Salvetti 2 Inserm U758, Ecole Normale Supérieure, IFR128, Lyon, France S. Adriouch S. Adriouch 1 Inserm U905, Institute for Biomedical Research, University of Rouen, Rouen, France O. Boyer O. Boyer 1 Inserm U905, Institute for Biomedical Research, University of Rouen, Rouen, France Abstract While skeletal muscle can be the target of several autoimmune diseases (myositis), the physiological mechanisms of tolerance to muscle-specific proteins remains mostly unknown. To investigate this issue, we previously developed transgenic (Tg) SM-Ova mice that express ovalbumin (Ova) selectively in skeletal muscle and showed lack of central thymic deletion of Ova-specific lymphocytes in anti-OVA TCR (OT-I or OT-II) crossed with SM-Ova mice. We now investigate the hypothesis of peripheral deletion. B6 mice strongly responded to AAV-Ova immunization (H2-Kb/Ova257-264 pentamer staining and rejection of Ova-expressing tumours). In contrast, SM-Ova mice did not develop any detectable Ova-specific CD8+ T cell response. PC-61 depletion of CD4+CD25+ Tregs did not restore response to rAAV-Ova in SM-Ova mice. Lack of Ova CD8+ T cell response in SM-Ova mice was also observed after lentivirus-Ova or VSV-Ova immunization (yet, SM-Ova mice developed normal levels of VSV-NP-specific CD8+ T cells and survived VSV-Ova infection). Also, no Ova-specific CD8+ T cell response was observed after AAV-Ova immunization of T-cell deficient mice adoptively transferred with SM-Ova T cells. Adoptively-transferred anti-Ova OT-I CD8+ T cells responded to lentivirus-Ova immunization in SM-Ova, indicating lack of dominant tolerance in the Ova-expressing recipient. Interestingly, in contrast to other models of tissue-specific Ova-expressing Tg mice, e.g. pancreatic beta-cells or intestinal cells, the activated OT-I cells did not cause myositis in SM-Ova mice, suggesting that muscle tissue display a higher degree of resistance to autoimmunity. Together, these results indicate that tolerance to a muscle-expressed protein involves the peripheral deletion of autoantigen-responsive CD8+ T cells. PP-072-11 A “memory” model of experimental autoimmune encephalomyelitis: implications for the development of disease modifying therapies for multiple sclerosis R. C. Knox R. C. Knox Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom C. Chung C. Chung Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom M. D. Leech M. D. Leech Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom S. M. Anderton S. M. Anderton Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom Abstract Experimental autoimmune encephalomyelitis (EAE) is a T cell driven autoimmune disease of the central nervous system (CNS) and is a model for multiple sclerosis (MS). It is important for the translation of candidate therapeutics that the pathology and clinical manifestations of EAE relate as accurately as possible to the human disease. The majority of MS cases present with an initial relapsing-remitting cycle which can often advance to a progressive course, whereas many EAE models exhibit a monophasic disease that spontaneously remits. Remission in EAE has been attributed to the induction of Foxp3+ cells in the CNS, the presence of which prevents subsequent re-induction of disease. Therefore, these models do not permit the study of antigen-experienced cells outside the context of active disease, and which may be present during remission of MS. Our studies demonstrate that primary immunisation with a CNS-derived peptide in adjuvant containing CpG can lead to the generation of antigen-experienced T cells. Upon secondary immunisation of peptide in complete Freund's adjuvant, these antigen-experienced cells are capable of inducing EAE with an early onset, increased severity and chronic disease course. We report the characteristics of this “memory” model and highlight the use of such a valuable tool in the development of therapeutics aimed at preventing or inhibiting disease relapse in MS. PP-072-12 Efficient expansion of Ag-specific Foxp3 regulatory T cells and protection against experimental autoimmune encephalomyelitis by treatment with B lymphocytes pulsed with antigen coupled to cholera toxin B subunit J. Sun J. Sun 1 Institute of Biomedicine (Department of Microbiology and Immunology), University of Gothenburg, Göteborg, Sweden C. Czerkinsky C. Czerkinsky 2 International Vaccine Institute (IVI), Seoul, Republic of Korea J. Holmgren J. Holmgren 1 Institute of Biomedicine (Department of Microbiology and Immunology), University of Gothenburg, Göteborg, Sweden Abstract We recently described the importance of B lymphocytes in induction of antigen (Ag)-specific oral tolerance and the associated increase in CD4+Foxp3+ regulatory T cells (Tregs) after mucosal administration of Ag conjugated to cholera toxin B subunit (CTB) (Sun et al. J Immunol. 2008;181:8278). We have now further assessed the effects of B cells pulsed in vitro with Ag/CTB conjugate on the induction of Ag-specific Tregs both in vitro and after adoptive transfer in vivo. We found a strong increase in Tregs when naive T cells were co-cultured in vitro with B cells pulsed with OVA/CTB, and the generated Tregs could effectively suppress CD25-CD4+ effector T cells (Teffs) in secondary in vitro cultures. A strong increase in Tregs was also seen in vivo in recipients after adoptive transfer of Ag/CTB pulsed B cells. Further, adoptive transfer of B cells pulsed with myelin oligodendrocyte glycoprotein (MOG) peptide35-55 conjugated to CTB efficiently (i) suppressed MOG-specific T cell proliferation and IL-17 and IFN-gamma production, (ii) increased Foxp3+CD4+ Tregs in draining lymph nodes and (iii) protected against the development of experimental autoimmune encephalomyelitis (EAE); similar effects were seen also when the B cell treatment was given “therapeutically” to mice with already on-going EAE. Our results show that B cells pulsed in vitro with relevant Ag/CTB conjugates followed by reinfusion of the treated B cells can be used to induce Ag-specific suppression of autoimmune disease. PP-072-13 TLR-2-activated B-cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing regulatory Tr-1 cells in a contact-dependent manner A. Sayi A. Sayi Institute of Molecular Cancer Research, Zurich, Switzerland A. Mueller A. Mueller Institute of Molecular Cancer Research, Zurich, Switzerland Abstract Regulatory function of B-cells has been shown in autoimmune pathologies and chronic inflammatory conditions such as autoimmune encephalomyelitis, arthritis and inflammatory bowel disease. We show that B-cells can also function in counter-regulation of adaptive immune responses to bacterial pathogens. Using mouse models of infection with the gastrointestinal pathogen Helicobacter felis, we found that B-cells are activated by Helicobacter TLR-2 ligands to become efficient inducers of CD4+CD25+IL-10+ T regulatory-1-like cells. Tr-1 conversion depends on TCR signalling and a direct T-/B-interaction through CD40/CD40L. B-cell-induced Tr-1 cells suppress excessive gastric immunopathology and prevent Helicobacter-induced gastric cancer precursor lesions such as atrophic gastritis and intestinal metaplasia. Adoptive co-transfer of B-cells and Tr-1 cells restores a normal gastric mucosal architecture in Myd88−/− mice. Our findings describe a novel mechanism of Tr-1 cell generation and function in a clinically relevant disease model. PP-072-14 Iloprost-treated dendritic cells modulate T-cell differentiation in vitro J. Suen J. Suen 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Microbiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan P. Kuo P. Kuo 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Microbiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Abstract Iloprost, a stable prostaglandin I2 (PGI2) analog, is a safe and well-accepted medication for pulmonary arterial hypertension. It has been shown that iloprost reduce inflammatory responses in OVA-induced allergic mouse model via inhibition of airway dendritic cell (DC) function. Iloprost also inhibits proinflammatory cytokine secretion and T-cell stimulatory activity of bone marrow-derived DCs (BMDCs) in an PGI2 receptor-dependent manner. However, little is known about whether PGI2 could direct T-cell differentiation through DC modulation. In this study, we characterized the tolerogenic properties of iloprost-treated BMDCs and then examined T-cell differentiation pattern mediated by iloprost-treated BMDCs. Our study showed that iloprost inhibited inflammatory cytokines (IL-12p70, TNF-α, IL-6, IL-23) expression and increased anti-inflammatory cytokine (IL-10) production of BMDCs. However, iloprost did not affect TGF-β expression level secreted by BMDCs. In addition, iloprost-treated BMDCs displayed semi-mature phenotype and exhibited little Ag-specific T-cell stimulatory activity. Furthermore, iloprost-modulated BMDCs increased the CD4+Foxp3+ T cell differentiation and inhibited Th1 and Th2 differentiation from naïve T cells in vitro. These data suggest that the PGI2 may modulate adaptive responses, at least in part, through innate immunity. PP-072-15 Analysis of regulatory CD4+ T cell subsets induced by oral administration of Lactobacillus gasseri OLL2809 in orally tolerized DO11.10 mice A. Yoshida A. Yoshida 1 Dept. of Appl. Biol. Chem., Univ. Tokyo, Tokyo, Japan K. Yamada K. Yamada 1 Dept. of Appl. Biol. Chem., Univ. Tokyo, Tokyo, Japan 2 Nihon Univ. School of Dentistry, Tokyo, Japan S. Hachimura S. Hachimura 3 Res. Cent. for Food Safety, Univ. Tokyo, Tokyo, Japan T. Sashihara T. Sashihara 4 Food Sci. Inst., Meiji Dairies Co., Tokyo, Japan S. Ikegami S. Ikegami 4 Food Sci. Inst., Meiji Dairies Co., Tokyo, Japan M. Shimizu M. Shimizu 1 Dept. of Appl. Biol. Chem., Univ. Tokyo, Tokyo, Japan M. Totsuka M. Totsuka 1 Dept. of Appl. Biol. Chem., Univ. Tokyo, Tokyo, Japan Abstract Purpose: Food allergy which causes a serious problem in infants might be prevented or ameliorated by inducing oral tolerance appropriately. We found that suppression of proliferative response and IL-2 production of spleen CD4+ T cells from DO11.10 mice following oral tolerance induction was enhanced by feeding Lactobacillus gasseri OLL2809 (LG2809). In the present study, we aimed to analyze regulatory CD4+ T cell subsets induced by administering LG2809. Methods: Female DO11.10 mice were administered saline or 1 mg/day of live LG2809 by gavages for 12 days. The mice were fed 20% ovalbumin (OVA) in drinking water ad libitum in the last 5 days. Splenic CD4+ T cells were prepared by MACS and further analysis and purification of CD4+ T cell subsets were performed by flow cytometory. Sorted CD4+ T cell subsets were incubated with antigen-presenting cells and OVA peptide with or without responder CD4+ T cells from DO11.10 spleen cells. IL-2 and IL-10 levels of culture supernatants were measured by ELISA. Results: Oral administration of LG2809 increased the population of CD62Llow CD44high CD4+ T cells, which had been found to be enlarged following oral tolerance induction and to secrete a large amount of IL-10. CD62Llow CD44high T cells sorted from mice fed OVA and LG2809 had stronger suppressive activity and higher IL-10 production than the same subset from mice fed OVA. The results suggested that LG2809 enhanced the induction of oral tolerance by both increasing the number of T cells in the subset with suppressive and IL-10-producing activity, and enhancing the suppressive activity of them. PP-072-16 Critical roles of GRAIL in T cell activation and tolerance R. Nurieva R. Nurieva 1 MD Anderson Cancer Center, Houston, TX, United States S. Zheng S. Zheng 2 National Defense Medical Center, Taipei, Taiwan W. Jin W. Jin 1 MD Anderson Cancer Center, Houston, TX, United States S. Sun S. Sun 1 MD Anderson Cancer Center, Houston, TX, United States G. Lozano G. Lozano 1 MD Anderson Cancer Center, Houston, TX, United States C. Dong C. Dong 1 MD Anderson Cancer Center, Houston, TX, United States Abstract T lymphocyte activation is tightly regulated to avoid autoimmunity. Gene related to anergy in lymphocytes (Grail) encodes an endosomal E3 ubiquitin ligase, whose expression has been associated with induction of T cell tolerance in vitro. In order to understand the physiological function of GRAIL in immune regulation, we have generated and analyzed Grail-deficient mice. We found that GRAIL is not required in the development of T lymphocytes but is required for their proper activation and function. Naïve T cells lacking GRAIL exhibited greatly enhanced proliferation and cytokine production after TcR activation and did not depend on CD28 and ICOS for their effector cytokine expression. Naïve CD4+ T cells from Grail-deficient mice were less efficient in down-regulation of their TcR/CD3 expression following TcR activation. In vivo, Grail-deficient mice were resistant to immune tolerance induction and when compared to the wild-type mice, exhibited greater susceptibility to autoimmune diseases. GRAIL is thus a critical regulator of T cell function and tolerance. The work is supported by research grants from NIH and a Scientist Development Grant from the American Heart Association. PP-072-17 Phagocytosis to apoptotic bodies induces transformation from DC to DCreg Q. Wang Q. Wang 1 Department of Immunology, Taishan Medical College, Tai'an, Shandong, China K. Zhong K. Zhong 2 School of Medicine, Tsinghua University, Beijing, China D. Chen D. Chen 2 School of Medicine, Tsinghua University, Beijing, China Y. Xu Y. Xu 1 Department of Immunology, Taishan Medical College, Tai'an, Shandong, China M. Zhang M. Zhang 2 School of Medicine, Tsinghua University, Beijing, China W. Song W. Song 1 Department of Immunology, Taishan Medical College, Tai'an, Shandong, China Abstract It is well known that T cells are restricted by activation-induced cell death (AICD), which contributes to immune homeostasis and peripheral tolerance. The underlying mechanisms for AICD induced tolerance remain poorly understood. We described here that OVA-specific CD4+ T cells underwent apoptosis following activation stimulated by OVA-loaded mature dendritic cells (mDCs). After phagocytosis of apoptotic CD4+ T cells, the phenotype and functions of DCs transformed to that of regulatory DCs (DCregs). DCregs secreted enormous amount of IL-10, TGF-β and NO after LPS or IFN-γ stimulation. Importantly, these apoptotic-body-induced DCregs are characterized by inhibiting mDC-induced CD4+and CD8+ T cell proliferation in vitro compared to DCs. We also observed that these DCregs significantly inhibited OVA-specific CD4+T and CD8+T cells proliferation in vivo by cell transfer assay. The NO produced by DCregs is responsible for the arrest of T cell proliferation, because the addition of NO synthetase inhibitor PBIT reversed the DCregs inhibition of CD4+ T cell proliferation. These results indicated that AICD of T cells in immune response can induce the generation of DCregs which can inhibit the proliferation of lymphocytes by NO directly and keep the homeostasis of immune system. This work supported by the fund from NCSF, China (30872322) PP-072-18 The function of B220+ lymphoid cells that ectopically expressed keratin 5 T. Hanafusa T. Hanafusa Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, Japan H. Azukizawa H. Azukizawa Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, Japan I. Katayama I. Katayama Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, Japan Abstract Immunological tolerance against peripheral self-antigen is maintained by thymic epithelial cell and dendritic cell (DC) by clonal deletion of autoreactive T cell. Recent report showed that peripheral self-antigen is also expressed in the secondary lymphoid organ under autoimmune regulator gene (Aire). To study the role of ectopic epidermal antigen expression, K5-Cre x CAG-CAT-EGFP double transgenic mice that express enhanced green fluorescence protein (GFP) under the control of keratin 5 promoter were employed. Keratin 5 is a peripheral tissue-specific antigen expressed in mainly expressed in epidermal keratinocyte. This mouse allows us fate mapping of keratin 5 expressing cell. Initially, we found that migratory DC contains low amount of GFP (GFPlow) in skin-draining lymph node (LN), indicating that epidermal GFP is transported by dendritic cells from skin to draining LN. Unexpectedly, GFPhigh cells distinct from migratory DC were found in not only skin-draining LN, but also mesenteric LN, spleen and peripheral blood. Surprisingly, their fluorescence intensity was much higher than that of GFPlow migratory DC. Kerartin 5 expression was hardly detected in this GFPhigh cell, whereas Cre-mediated recombination was identified in sorted GFPhigh cells, suggesting that GFP is self-expressed in the cytoplasm under transiently activated keratin 5 promoter. Although GFPhigh cells expressed CD45R (B220)+but IgD-, mPDCA-1-, these cells stimulated CD8+ or CD4+ T cells comparable to plasmacytoid DC (pDC) in vitro, indicating that B220+ lymphoid cells which ectopically expressed keratin 5 might have a function of antigen-presentation. PP-072-19 Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR-L interaction, IL-10 and TGF-beta J. Satoguina J. Satoguina 1 MRC(UK) The Gambia, Banjul, Gambia 2 IMMIP, Bonn, Germany T. Adjobimey T. Adjobimey 2 IMMIP, Bonn, Germany K. Arndts K. Arndts 2 IMMIP, Bonn, Germany J. Hoch J. Hoch 3 Institute of experimental haematology and transfusion med., Bonn, Germany J. Oldenburg J. Oldenburg 3 Institute of experimental haematology and transfusion med., Bonn, Germany L. Layland L. Layland 2 IMMIP, Bonn, Germany A. Hoerauf A. Hoerauf 2 IMMIP, Bonn, Germany Abstract Regulatory T cells exert their function through the modulation of both T and B cell responses. Our previous studies demonstrated that IL-10-producing Treg (Tr1) can induce B cells to secrete IgG4 in a cell-contact-dependent manner. The benefit of such noninflammatory B-cell responses is apparent in the hyporesponsive state of patients with parasitic infections such as Onchocerciasis, which overwhelm the body with several antigens. Here, we investigated the mechanisms involved to induce IgG4, within B:Tr-cell co-cultures, using IL-10-producing antigen-specific regulatory T cell lines and clones (Tr-TCC) from human PBMC. During the generation process, we found that increasing Foxp3 levels in regulatory T cell lines correlated with their ability to induce IgG4 in B cells. Using Tr-TCC, we found that blocking glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) molecules selectively prevented IgG4 production as did neutralizing Ab to glucocorticoid-induced tumour necrosis factor receptor-related protein ligand (GITR-L), IL-10 and TGF-b. Furthermore, the prevention of IgG4 induction by anti-GITR Ab was reversed by excess rIL-10 but not rTGF-beta. In contrast, anti-ICOS and anti-CTLA-4 Abs had no effect. When compared with Tr-TCC, freshly isolated CD41CD251 T cells, but not effector T cell populations, induced low levels of IgG4, which were also blocked by anti-GITR and anti-GITR-L Ab. Thus, the mechanism of IgG4 induction by regulatory cells involves GITR-GITR-L interactions, IL-10 and TGF-beta. PP-072-20 Peripheral B cell tolerance in a novel mouse model I. Wu I. Wu 1 Sanford Burnham Medical Institute and UCSD, La Jolla, CA, United States T. Hurtado de Mendoza T. Hurtado de Mendoza 2 The Salk Institute, La Jolla, CA, United States R. C. Rickert R. C. Rickert 1 Sanford Burnham Medical Institute and UCSD, La Jolla, CA, United States Abstract Tolerance mechanisms to distinguish between self and foreign protein need to be in place throughout B cell development. The mechanisms that operate during developing B cells in the bone marrow have been established, while tolerogenic mechanisms in the periphery remains unclear. Published studies addressing peripheral B cell have yielded conflicting results ranging from B cell elimination to no detectable effect on autospecific B cells. These disparate findings could be due in part to differing locations of self-antigen expression, in addition to issues of BCR signal strength. We have successfully developed a novel mouse model that expresses low-affinity “self-antigen” primarily in the secondary lymphoid organs where B cells naturally reside and immune responses occur. Using immunoglobulin knock-in transgenic B cells, we are in the process of defining the parameters that mediate effective censoring of autoreactive B cells in the peripheral lymphoid tissues. PP-072-21 The role of the Ca2+ signal in the regulation of T cell activation and anergy Y. Adachi Y. Adachi Dept. Appl. Biol. Chem., Tokyo Univ. Agric. Technol, Tokyo, Japan M. Hattori M. Hattori Dept. Appl. Biol. Chem., Tokyo Univ. Agric. Technol, Tokyo, Japan T. Yoshida T. Yoshida Dept. Appl. Biol. Chem., Tokyo Univ. Agric. Technol, Tokyo, Japan Abstract The Ca2+ signal has been reported to play a key role in T cell activation and anergy induction. However, how the signal determines the induction of anergy or activation has not been clarified. In this study, we examined the mechanism for regulating T cell activation and anergy by the Ca2+ signal in vitro and in vivo. We found that Th1 cells were both activated and anergized depending on the concentraion of cyclosproin A (CsA) when the cells were stimulated with anti-CD3 mAb and CsA in vitro, indicating that the intensity of the Ca2+ signal can determine T cell activation and anergy. We then examined whether this regulation could be applied for oral tolerance. We observed that T cell response of the mice that had been fed with an antigen was lower than that of control mice, while the response of the mice that had been treated with CsA during tolerance induction was higher than that of control mice. This result corresponded well with the in vitro observation. Next, we examined whether a stimulation by ionomycin, which induced the Ca2+ signal in T cells, could induce activation and anergy depending on the concentration. Interestingly, T cell activation was not apparent at any concentration of ionomycin. These results indicate that the balance between the Ca2+ signal and other signals which can be also induced by anti-CD3 stimulation, but not the actual intensity of the Ca2+ signal or the presence of co-stimulation, plays an important role in regulating T cell activation and anergy. PP-072-22 Antigen density controls the function of activated memory CTLs R. Wolchinsky R. Wolchinsky Technion, Haifa, Israel K. Oved K. Oved Technion, Haifa, Israel Y. Reiter Y. Reiter Technion, Haifa, Israel Abstract CTLs act as the effector arm of the cell-mediated immune system to kill undesirable cells. Two processes regulate these effector cells to prevent self reactivity: a thymic selection process that eliminates autoreactive clones and a multistage activation or priming process that endows them with a license to kill cognate target cells. Hitherto no subsequent regulatory restrictions have been ascribed for properly primed and activated CTLs that are licensed to kill. We have shown that CTLs possess a novel postpriming regulatory mechanism(s) that influences the outcome of their encounter with cognate target cells. This mechanism, which its machinery we currently explore, gauges the degree of Ag density, whereupon reaching a certain threshold significant changes occur that induce anergy in the effector T cells. The biological consequences of this Ag-induced postpriming control includes alterations in the expression of cell surface molecules that control immunological synapse activity and cytokine profiles and induce retarded cell proliferation. Most profound is genome-wide microarray analysis that demonstrates changes in the expression of genes related to membrane potential, TCR signal transduction, energy metabolism, and cell cycle control. Thus, a discernible and unique gene expression signature for anergy as a response to high Ag density has been observed. Consequently, activated T cells possess properties of a self-referential sensory organ. These studies identify a new postpriming control mechanism of CTL with anergenic-like properties. This mechanism extends our understanding of the control of immune function and regulation such as peripheral tolerance, viral infections, antitumor immune responses, hypersensitivity, and autoimmunity. PP-072-23 Immunoregulatory properties of adult tissue specific stem cells M. Krulova M. Krulova 1 Faculty of Science, Charles University, Prague, Czech Republic 2 Institute of Molecular Genetics, Academy of Sciences, Prague, Czech Republic K. Pokorna K. Pokorna 1 Faculty of Science, Charles University, Prague, Czech Republic 2 Institute of Molecular Genetics, Academy of Sciences, Prague, Czech Republic J. Prochazkova J. Prochazkova 1 Faculty of Science, Charles University, Prague, Czech Republic 2 Institute of Molecular Genetics, Academy of Sciences, Prague, Czech Republic A. Zajicova A. Zajicova 2 Institute of Molecular Genetics, Academy of Sciences, Prague, Czech Republic V. Holan V. Holan 1 Faculty of Science, Charles University, Prague, Czech Republic 2 Institute of Molecular Genetics, Academy of Sciences, Prague, Czech Republic Abstract The primary role of adult stem cells (SC) in a living organism is to maintain and repair the tissue in which they are found. In addition to their role of tissue regeneration they exert powerful immunosuppressive properties. Stem cells which have been shown to be responsible for renewal of ceased or damaged corneal surface are located in the basal region of the limbus. The deficiency of limbal stem cells (LSC) leads to conjunctivization and corneal opacification followed by an irreversible loss of visual function. We demonstrate that a population of mouse limbal cells highly enriched for cells expressing markers and charateristics of LSCs suppresses in a dose-dependent manner the proliferation of lymphocytes and significantly inhibits the production of proinflammatory cytokines by activated T cells. The suppression was mediated by soluble factor(s) and did not affect early cell activation. LSCs were even more suppressive than mesenchymal stem cells or natural regulatory T cells. In addition, the cells expressing markers and characteristics of LSC had significantly higher levels of mRNA for Fas ligand and for the antiapoptotic molecules Mcl-1, XIAP, and survivin than other limbal cell populations. LSCs were also more resistant to staurosporin-induced apoptotic cell death and to cell-mediated cytotoxic reaction than other limbal cells. Collectively, these results suggest that SC isolated from fresh adult limbal tissue possess immunomodulatory properties and inhibit proinflammatory immune reactions. Simultaneously, these cells express high levels of mRNA for antiapoptotic molecules, which can protect them against cell-mediated cytotoxic reactions and various apoptosis-inducing agents. PP-072-24 The role of autoantigen in influencing the avidity and activation of myelin-responsive CD8+ T cells M. Leech M. Leech University of Edinburgh, Edinburgh, United Kingdom C. Sweenie C. Sweenie University of Edinburgh, Edinburgh, United Kingdom S. Anderton S. Anderton University of Edinburgh, Edinburgh, United Kingdom Abstract Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). CD8+ T cells may have a pathogenic role in MS, given their appearance within CNS lesions, but how myelin-responsive CD8+ T cells are influenced by physiological levels of autoantigen is unclear. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), the influence of endogenous exposure to myelin oligodendrocyte glycoprotein (MOG) was investigated by comparison of wild-type (WT) mice with MOG-deficient (MOG−/−) counterparts. Using overlapping peptides of MOG, we found that both WT and MOG−/− mice responded only to the reported immunodominant region of MOG (residues 35-55). MOG−/− mice were more sensitive to immunization with the MOG35-55 peptide (enhanced IFN-γ and IL-17 secretion). This immunization regime induced expansion of both CD4+ and CD8+ T cells in both WT and MOG−/− mice. However, MOG−/− mice showed enhanced expansion specifically in the CD8+ fraction. CD8+ T cell lines (TCL) were developed from WT and MOG−/− mice. MOG−/− TCL secreted higher titres of IFN-γ than WT TCL, in response to the MOG35-55 peptide. Within this peptide, we identified a truncated epitope (p41-55) to which only MOG−/− TCL were responsive. Therefore, in the absence of tolerogenic exposure to endogenous MOG, highly sensitive MOG-responsive CD8+ T cells can persist. However, exhaustive attempts to use these CD8+ cells to induce pathology (EAE) in isolation proved unsuccessful. We conclude that tolerance to MOG seems to focus more on the CD8+ T cells repertoire, but it is the MOG-responsive CD4+ repertoire that drives EAE. PP-072-25 Design, synthesis and evaluation of quinazoline T cell proliferation inhibitors I. Sagiv I. Sagiv Hebrew University Jerusalem Israel, Jerusalem, Israel E. Weiss Lavi E. Weiss Lavi Hebrew University Jerusalem Israel, Jerusalem, Israel A. Levitzki A. Levitzki Hebrew University Jerusalem Israel, Jerusalem, Israel Abstract We present here a novel class of quinazoline molecules that inhibit T cell proliferation. The most potent compound N-p-tolyl-2-(3,4,5-trimethoxyphenyl)quinazolin-4-amine (S101) and its close analogs were found to inhibit the proliferation of T cells from human peripheral blood mononuclear cells (PBMC) and Jurkat cells, with IC50 in the sub-micro molar range. The inhibitor induced G2 cell cycle arrest but did not inhibit IL-2 secretion. The inhibitor did not affect proliferation of non-hematopoietic cells. This new class of specific T cell proliferation inhibitors may serve as lead molecules for the future development of agents aimed at diseases in which T cell signaling plays a role and may be used to induce tolerance to grafted tissues or organs. PP-072-26 Lymphopenia-induced proliferation in the absence of functional Autoimmune Regulator induces colitis in mice E. Kekalainen E. Kekalainen 1 Haartman institute, Dept. of Immunology, University of Helsinki, University of Helsinki, Finland M. Lehto M. Lehto 1 Haartman institute, Dept. of Immunology, University of Helsinki, University of Helsinki, Finland E. Smeds E. Smeds 1 Haartman institute, Dept. of Immunology, University of Helsinki, University of Helsinki, Finland N. Pöntynen N. Pöntynen 2 National Institute of Health, Department of Molecular Medicine, Helsinki, Finland L. H. Rossi L. H. Rossi 1 Haartman institute, Dept. of Immunology, University of Helsinki, University of Helsinki, Finland I. Ulmanen I. Ulmanen 2 National Institute of Health, Department of Molecular Medicine, Helsinki, Finland A. Miettinen A. Miettinen 3 HUSLAB, Department of Immunology, Helsinki University Hospital, Helsinki, Finland T. P. Arstila T. P. Arstila 1 Haartman institute, Dept. of Immunology, University of Helsinki, University of Helsinki, Finland Abstract Autoimmune regulator (Aire) has been shown to promote negative selection of autoreactive thymocytes, but it is also expressed in peripheral tissues and can drive deletional tolerance of mature T cells. Despite recent progress in research, the full importance or range of Aire's peripheral function is not known. Our aim was to dissect the role of peripheral Aire in the regulation of T cell tolerance and homeostasis. Lymphopenia-induced T cell proliferation is driven by self and commensal antigens and its used generally as a model to predispose mice to inflammation and autoimmunity. We transferred lymph node cells from syngeneic wildtype donors into lymphopenic recipients with or without functional Aire, and monitored the recipients for clinical symptoms of disease and immunopathological changes. The transferred wild-type cells triggered disease in Aire−/− but not in Aire+/+ lymphopenic mice. The disease was characterized by diarrhoea and colitis, and in some recipients pancreatitis, gastritis, and hepatitis was also found. As a sign of inflammation, the Aire−/− recipients had significantly higher levels of the acute phase serum amyloid protein A. We also did cell transfers from Aire-deficient donors to wild-type recipients and some disease components of the donors were transferable. However, these recipients stayed clinically healthy even though the transferred cells were hyperproliferative. Our results indicate that peripheral expression of Aire has functions distinct from those of thymic Aire and identify Aire as an important regulator of peripheral T cell homeostasis in the gastrointestinal tissues. PP-072-27 Anergy in human regulatory T cells, HOZOTs, is maintained by the continuous stimulation through TCR and costimulatory molecules K. Tsuji-Takayama K. Tsuji-Takayama 1 Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan T. Otani T. Otani 1 Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan M. Yamamoto M. Yamamoto 1 Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan A. Okochi A. Okochi 1 Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan M. Takeuchi M. Takeuchi 1 Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan F. Yamasaki F. Yamasaki 2 Kurashiki Medical Center, Kurashiki, Japan T. Ito T. Ito 3 First Department of Internal Medicine, Kansai Medical University, Osaka, Japan S. Nakamura S. Nakamura 1 Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan M. Kibata M. Kibata 1 Cell Biology Institute, Research Center, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan Abstract In addition to regulatory function, anergy is a central hallmark of Treg cells. As mechanisms of the anergy, the lack of costimulatory signaling and/or the expression of E3 ubiquitin ligases are known to be involved in the defects of TCR response in T helper cells. FOXP3 also plays a key role in the anergy by repressing both IL-2 and IFN-γ production in Treg cells. However, there are distinct types of Tregs, in which the repression was observed in IL-2 but not IFN-γ production, and their mechanisms for the IL-2 repression could be FOXP3-independent. To examine such mechanisms, we used FOXP3low human Treg cells, HOZOTs, (recently designated as Tchreg cells due to their multifunctional property), which were established and maintained by the cultivation with mouse stromal cells. HOZOTs produced IL-10 and IFN-γ at high levels but IL-2 at a low or no level by the TCR stimulation. The selective IL-2 repression in HOZOTs was maintained by the cultivation with stromal cells but cancelled under the stromal-free conditions. Blocking experiments using antibodies (anti-mouse MHC-class I mAb or anti-B7-1 mAb) for stromal cells revealed the involvement of TCR/costimulatory signaling in the anergy maintenance. Furthermore, anti-CD3 mAb cross-linked L cells also maintained the anergy. The enforced B7-1 expressing stromal cells as well as anti-CD28 mAb/anti-ICOS mAb cross-linked L cells enhanced the IL-2 repression with TCR stimulation. In conclusion, the continuous TCR/costimulatory signaling maintains the anergic state of HOZOT in FOXP3-independent manner, making contrast to that of FOXP3+ Tregs or T helper cells. PP-072-28 Mechanism of Th-cell tolerance induced with the tolerogenic protein antigen conjugated with polyethylene glycol M. Obata M. Obata 1 Toin Human Science and Technology Center, Toin University of Yokohama, Yokohama, Japan R. Fujiwara R. Fujiwara 1 Toin Human Science and Technology Center, Toin University of Yokohama, Yokohama, Japan T. Fujii T. Fujii 1 Toin Human Science and Technology Center, Toin University of Yokohama, Yokohama, Japan Y. Kodera Y. Kodera 1 Toin Human Science and Technology Center, Toin University of Yokohama, Yokohama, Japan M. Ohtsuji M. Ohtsuji 1 Toin Human Science and Technology Center, Toin University of Yokohama, Yokohama, Japan T. Shirai T. Shirai 2 Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan S. Hirose S. Hirose 2 Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan H. Nishimura H. Nishimura 1 Toin Human Science and Technology Center, Toin University of Yokohama, Yokohama, Japan Abstract It has long been known that administration of protein antigens conjugated with polyethylene glycol (PEG) induce antigen-specific immune tolerance. Classical studies demonstrated the carrier-specific Th cell tolerance as induced with PEG-carrier proteins. Nevertheless, the cellular and molecular mechanism underlying these observations has been obscure. We tested the tolerogenic PEG-OVA conjugate on the ontogeny and differentiation of OVA-specific transgenic CD4+ T cells. Administration of PEG-OVA induced robust proliferative response of CFSE-labeled CD4+ cells from OT-II cells leading to the anergic Th cell functions in the periphery. These observations were analogous to those observed for OT-II CD4+ T cells as transferred into histocompatible mice with systemic expression of transgenic OVA, suggesting that the markedly enhanced stability of PEG-OVA in the circulation is the basis of its tolerogenic capacity. Intriguingly, tolerogenic capacity was lost when the native conformational structure of OVA in the PEG-OVA conjugate was denatured, and tolerogenic capacity of the conjugate appeared to be dependent on the retention of B-cell epitopes in PEG-OVA. In contrast to normal strains of mice such as C57BL/6, autoimmuno disease-prone New Zealand Black (NZB) mice were genetically defective to induce OVA-specific tolerance when administered with PEG-OVA. We mapped the loci linked to this defective tolerance in (C57BL/6 x NZB) F2-intercross mice and found that the major responsive locus on the telomeric region of chromosome 1. PEG-OVA conjugate provides a useful model tolerogen and we are currently trying to identify the gene responsible for the peripheral immune tolerance. PP-072-29 Cellular mechanism in narrowband UVB-induced immunosuppression K. Taguchi K. Taguchi Division of dermatology, Department of Internal related, Kobe University Graduate School of Medicine, Kobe, Japan A. Fukunaga A. Fukunaga Division of dermatology, Department of Internal related, Kobe University Graduate School of Medicine, Kobe, Japan K. Ogura K. Ogura Division of dermatology, Department of Internal related, Kobe University Graduate School of Medicine, Kobe, Japan C. Nishigori C. Nishigori Division of dermatology, Department of Internal related, Kobe University Graduate School of Medicine, Kobe, Japan Abstract Narrow-band UVB (NB-UVB), with a peak wavelength of 311nm, has been shown to be effective for treating various cutaneous diseases such as psoriasis and atopic dermatitis. However, the action mechanism of NB-UVB therapy is still unclear. In this study we investigated on the cellular mechanism in NB-UVB induced immune suppression and regulation. It is generally believed that UV exposure alters the morphology and function of epidermal Langerhans (LC), which plays a role in UV-induced immune suppression. It is known that epidermal Langerhans cells (LCs) and dermal dendritic cells (dDCs) play antigen-presenting roles in the skin. In contrast, it is recently suggested that epidermal LCs are especially related with immunoregulation and immunosuppression. We previously reported that epidermal LCs migrated to the regional lymph nodes by broadband-UVB (BB-UVB) irradiation and migrating LCs played an important role of cutaneous immunoregulation.On these backgrounds, we focused on the relationship between skin dendritic cells and NB-UVB-induced immunosuppression. First, local NB-UVB irradiation suppressed contact hypersensitivity response.We found that more epidermal LCs than dDCs migrated from skin to the draining lymph nodes after NB-UVB irradiation. In contrast, we noted that NB-UVB irradiation did not induce the expansion of regulatory T cells in the regional lymph nodes contrary to BB-UVB irradiation.Our findings indicate that NB-UVB-induced immunosuppression is caused by the predominant migration of epidermal LCs without an involvement of regulatory T cells. PP-072-30 Cross-linking Tim-1 with a novel partner inhibits T-cell activation and prevents allograft rejection through suppression of AKT and ERK1/2 phosphorylation G. Ding G. Ding 1 Institute of Organ Transplantation, Second Military Medical University, Shanghai, China X. Shi X. Shi 1 Institute of Organ Transplantation, Second Military Medical University, Shanghai, China L. Xiao L. Xiao 1 Institute of Organ Transplantation, Second Military Medical University, Shanghai, China H. Fu H. Fu 1 Institute of Organ Transplantation, Second Military Medical University, Shanghai, China F. Liu F. Liu 1 Institute of Organ Transplantation, Second Military Medical University, Shanghai, China X. Shen X. Shen 2 National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China Q. Wang Q. Wang 2 National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China Abstract T-cell immunoglobulin mucin proteins represent a newly discovered family of molecules that play critical roles in regulation of Th1 and Th2 immune responses. Tim-1 was originally identified as a cellular receptor for Hepatitis A virus which results in an inhibition of Th2 differentiation and leads to a reduction in the development of asthma and allergy. Tim-4 was latterly found as Tim-1 ligand expressed on APCs. However, the molecular mechanism of Tim family members involved in regulating T cell activation and differentiation remains unclear. To investigate the role of Tim-1 on T cell function, we expressed and purified recombinant human Tim-1 extracellular domain and IgG1 Fc fusion protein (Tim-1-Fc). We found that Tim-1-Fc can dramatically inhibit CD4+ and CD8+ T cell proliferation following stimulation by CD3+CD28 mAb and allogeniec MLR. Neither the freshly isolated nor activated mouse T cells were detected to express Tim-4 by FACS analysis, and the inhibitory effects were also not restored by TIM-4 mAb. In concert with the inhibition of T cells activation, IL-2 and IL-2 receptor (CD25) expression were significantly reduced. Western-blot analysis revealed that Tim-1 mediated its inhibitory effects on T cell proliferation by inhibiting AKT and ERK1/2 phosphorylation. In vivo administration of Tim-1-Fc significantly prolonged the cardiac allograft survival.These results suggest that Tim-1 inhibits T-cell activation through binding a novel partner on T cells other than Tim-4 and triggering a negative signal control of AKT and ERK1/2 phosphorylation. The data provide the evidences for the possibility of developing an immunosuppressive therapeutic for allograft rejection. PP-072-31 The negative costimulatory molecule B7H4 and B7H1 differentially regulate immunomodulation by Human bone marrow-derived mesenchymal stem cells Y. Gu Y. Gu 1 Key Laboratory of Stem Cell of Jiangsu Province, Institute of Medical Biotechnology, Suzhou University, Suzhou, China Q. Xue Q. Xue 2 Clinical Immunology Key Lab of Jiangsu Province at the First Affiliated Hospital of Suzhou University, Suzhou, Suzhou, China X. Zhang X. Zhang 1 Key Laboratory of Stem Cell of Jiangsu Province, Institute of Medical Biotechnology, Suzhou University, Suzhou, China Abstract Human bone marrow-derived mesenchymal stem cells (hBMSCs) possess immunosuppressive properties. Besides soluble factors produced by MSC, cell-cell contact is another important mechanism contributing to the immunosuppression effect. Previous reports suggested the negative co-inhibitor molecules PD-L1 (B7-H1) and B7-H4 were responsible to the BMSC immunomodulate effect on T cell activation and proliferation. To insight the difference and relation between these two molecules belonging to TNF superfamily, we measured the expression of these two molecules by immunofluorescence staining and FACS; compared their inhibit effect using neutralising anti-PD-L1 mAb and/or anti-B7-H4 mAb by observing the proliferation and activation of T cells, and measuring the level of TGF-β1 and IL-10 by ELISA when BMSC co-cultured with T cells stimulated by PHA or allogenic PBMCs (peripheral blood mononuclear cell). The result showed: B7-H4 was constitutively expressed on hBMSC, while B7-H1 was induced to be expressed on hBMSC in low level. Blocking studies revealed that B7H4 more significantly attenuated the inhibitory effects of hBMSCs on T-cell activation and proliferation than that of B7H1 in the result of flowcytometer assay of the CD4+CD25+, CD4+CD69+ and the 3H-TdR insert testing. Furthermore, less decreased secretion of TGF-β1 and IL-10 were found in the supernatant of the group by blocking B7H4 than that in the group by blocking B7H1. And these two molecules don't have synergia effect. These data suggested that B7H4 may be more important in the immunomodulating effect of hBMSCs on T cells, and they may act in different time course. PP-072-32 Suppressive effects of human embryonic stem cell, fetal-type and adult-type mesenchymal stem cells on peripheral blood mononuclear cells C. Chan C. Chan 1 Graduate Institute of Clinical Medical Science, Chang Gung University, Taoyuan, Taiwan 2 Department of Pediatrics, Taoyuan General Hospital, Taoyuan, Taiwan S. Liao S. Liao 3 Graduate Institute of Clinical Medical Science, Chang Gung University, Taouan, Taiwan, Taouan, Taiwan M. Kuo M. Kuo 4 Graduate Institute of Basic Medical Science, Chang Gung University, Taoyuan, Taiwan J. Huang J. Huang 5 Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan Abstract Mesenchymal stem cells (MSCs) were found to have immunomodulatory effects. Acquiring MSCs from bone marrow is invasive. Therefore, other practicable sources are urgently needed. This study compared the immunosuppressive potentials of human stem cells under identical experimental conditions. Peripheral blood mononuclear cells (PBMCs) suppression assay was used to assess the suppressive effects of fetal-type and adult-type-MSCs and human embryonic stem cells (hESCs) cultured with and without feeder cells. Carboxyfluoerescein diacetate succinimidyl ester assay was used to double check the results. The hESCs, fetal-type and adult-type-MSCs significantly inhibited PBMCs proliferation in dose-dependent manner. The immunosuppressive effects of hESCs decreased in feeder-free culture conditions. For a series of dosages, the average inhibition on PBMC proliferation by hESCs was 97-53 %, by fetal-type-MSCs it was 88-21% and by adult-type-MSCs it was 63%-19% (P<0.01). Besides, population doubling for fetal-type-MSCs was 2.58±0.065 and for adult-type-MSCs it was 1.37±0.065 (p<0.05). The population doubling times were 27.89±0.71 and 66.87±3.09 for fetal-type and adult-type-MSCs, respectively (p<0.05). Our study found that the suppressive effects on PBMCs by hESCs are significantly stronger than those by fetal-type-MSCs, and that those by fetal-type-MSCs are significantly stronger than those by adult-type-MSCs. Although hESCs are strong, specific cellular immunosuppressants, ethical considerations and teratoma formation are obstacles for clinical applications. We postulate that not only the ease for obtaining cells without adverse clinical consequences, but also their rapid proliferation, make fetal-type-MSCs ideal alternative candidates to BMSCs for cell-based therapies, especially for diseases associated with immune responses due to obvious immunosuppressive effects. PP-072-33 Study on the mechanisms of mucosal tolerance with a murine model of asthma K. Chu K. Chu 1 Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan B. Chiang B. Chiang 1 Graduate Institute of Immunology, National Taiwan University, Taipei, Taiwan 2 Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan 3 Allergy center, National Taiwan University Hospital, Taipei, Taiwan Abstract Asthma is one of the most common chronic airway inflammatory diseases. Allergen specific immunotherapy has been used in humans for allergic diseases treatment almost a century. The induction of immunological tolerance against non-pathogenic antigen is a phenomenon observed along the mucosa of the respiratory, gastrointestinal, and urogenital tract. However, the mechanism of mucosal tolerance is still unclear. Here, we use the oral administration of OVA protein for consecutive five days in mice and collect cells from Peyer's patches, MLN and spleen. Percentage of nature occurring Treg cells and suppression function are evaluate Mice fed with OVA 0.5 and 20 mg had relief on asthmatic syndrome, including Th2 cytokine production and eosinophil infiltrated in bronchoalveolar lavage fluid (BALF). Increased numbers of IL-10-producing or Foxp3+ CD4+ T cells are found in Peyer's patches, MLN and spleen of orally fed mice. Next, we determine the effect of B cells cultured with naive CD4+ T cells, which are called as TofB. Here, TofB cells have suppressive function on T cell proliferation. B cells isolated from MLN and Peyer's patches of mice oral fed OVA could generate TofB with suppressive function more than B cells from control group mice. The ability of B cells to generate regulatory T cells is through cell-cell contact and IL-10-dependent manner. We find out that oral feeding mice with antigen could increase both Foxp3+ and IL-10 producing Treg cells and this effect might maintain for a long time. © The Japanese Society for Immunology. 2010. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
TI - Peripheral tolerance and lymphocyte anergy (PP-072)
JF - International Immunology
DO - 10.1093/intimm/dxq252
DA - 2010-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/peripheral-tolerance-and-lymphocyte-anergy-pp-072-BzSmkxVkGk
SP - iv53
VL - 22
IS - Suppl_1_Pt_4
DP - DeepDyve
ER -