Microbiota-centered interventions to boost immune checkpoint blockade therapiesAlmonte, Andrew A.;Thomas, Simon;Zitvogel, Laurence
doi: 10.1084/jem.20250378pmid: 40261296
Immune checkpoint blockade therapies have markedly advanced cancer treatment by invigorating antitumor immunity and extending patient survival. However, therapeutic resistance and immune-related toxicities remain major concerns. Emerging evidence indicates that microbial dysbiosis diminishes therapeutic response rates, while a diverse gut ecology and key beneficial taxa correlate with improved treatment outcomes. Therefore, there is a growing understanding that manipulating the gut microbiota could boost therapy efficacy. This review examines burgeoning methods that target the gut microbiome to optimize therapy and innovative diagnostic tools to detect dysbiosis, and highlights challenges that remain to be addressed in the field.
Plasmodium falciparum infection induces T cell tolerance that is associated with decreased disease severity upon re-infectionMuñoz Sandoval, Diana;Bach, Florian A.;Ivens, Alasdair;Harding, Adam C.;Smith, Natasha L.;Mazurczyk, Michalina;Themistocleous, Yrene;Edwards, Nick J.;Silk, Sarah E.;Barrett, Jordan R.;Cowan, Graeme J.M.;Napolitani, Giorgio;Savill, Nicholas J.;Draper, Simon J.;Minassian, Angela M.;Nahrendorf, Wiebke;Spence, Philip J.
doi: 10.1084/jem.20241667pmid: 40214640
Immunity to severe malaria is acquired quickly, operates independently of pathogen load, and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance remains unknown. We used a human rechallenge model of falciparum malaria in which healthy adult volunteers were infected three times over a 12 mo period to track the development of disease tolerance in real-time. We found that parasitemia triggered a hardwired innate immune response that led to systemic inflammation, pyrexia, and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, a single infection was sufficient to reprogram T cell activation and reduce the number and diversity of effector cells upon rechallenge. Crucially, this did not silence stem-like memory cells but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerized hosts were thus able to prevent collateral tissue damage in the absence of antiparasite immunity.
Vaccination against influenza viruses annually: Renewing or narrowing the protective shield?Matz, Hanover C.;Ellebedy, Ali H.
doi: 10.1084/jem.20241283pmid: 40272481
Annual vaccines are recommended for the seasonal influenza virus. While yearly updates to the vaccine are necessary due to the constant evolution of influenza viruses, some studies have suggested repeat vaccination may result in a reduction in vaccine effectiveness in subsequent years. This review examines the available evidence that repeated annual influenza virus vaccination may have effects on future vaccine responses, and it synthesizes the available data with studies that may indicate potential immunological mechanisms underlying these effects. The goal is to examine the available literature to determine whether these mechanisms can be subverted to improve seasonal influenza virus vaccine efficacy.
Prenatally derived macrophages support choroidal health and decline in age-related macular degenerationFortmann, Seth D.;Frey, Blake F.;Rosencrans, Robert F.;Adu-Rutledge, Yvonne;Ready V, Edgar;Kilchrist, Kameron V.;Welner, Robert S.;Boulton, Michael E.;Saban, Daniel R.;Grant, Maria B.
doi: 10.1084/jem.20242007pmid: 40261298
Hallmark findings in age-related macular degeneration (AMD) include the accumulation of extracellular lipid and vasodegeneration of the choriocapillaris. Choroidal inflammation has long been associated with AMD, but little is known about the immune landscape of the human choroid. Using 3D multiplex immunofluorescence, single-cell RNA sequencing, and flow cytometry, we unravel the cellular composition and spatial organization of the human choroid and the immune cells within it. We identify two populations of choroidal macrophages with distinct FOLR2 expression that account for the majority of myeloid cells. FOLR2+ macrophages predominate in the nondiseased eye, express lipid-handling machinery, uptake lipoprotein particles, and contain high amounts of lipid. In AMD, FOLR2+ macrophages are decreased in number and exhibit dysfunctional lipoprotein metabolism. In mice, FOLR2+ macrophages are negative for the postnatal fate-reporter Ms4a3, and their depletion causes an accelerated AMD-like phenotype. Our results show that prenatally derived resident macrophages decline in AMD and are implicated in multiple hallmark functions known to be compromised in the disease.
Sympathetic axonogenesis promotes adenoid cystic carcinoma progressionChen, Chun-Hao;Reva, Boris;Katabi, Nora;Wizel, Avishai;Xu, Hongbo;Ho, Alan L.;Morris, Luc G.T.;Bakst, Richard L.;Parikh, Anuraag S.;Drier, Yotam;Deborde, Sylvie;Wong, Richard J.
doi: 10.1084/jem.20242250pmid: 40272482
Nerves are integral to the adenoid cystic carcinoma (ACC) microenvironment. The strong association of ACC with perineural invasion (PNI) is considered a hallmark of this disease. In human salivary ACC, we identify intratumoral, small-caliber, disorganized sympathetic nerves not observed in other salivary neoplasms. Norepinephrine or sympathetic ganglia explants enhance ACC proliferation in vitro. Two novel orthotopic ACC patient-derived xenograft (PDX) models recapitulate ACC morphology and demonstrate sympathetic innervation. Pharmacologic or surgical blockade of sympathetic nerves decreases ACC PDX growth. Bulk RNA sequencing of salivary ACC reveals correlations between noradrenergic nerve development signatures and worse patient survival. Metastatic ACC foci exhibit lower nerve signature gene expression levels than primary ACC. Sympathetic innervation in ACC is distinct from PNI and reflects tumor axonogenesis driven by noradrenergic neural development programs. These programs support ACC progression, are associated with poor prognosis, and may be inhibited as a therapeutic strategy.
Factor XII–driven coagulation traps bacterial infectionsNickel, Katrin F.;Jämsä, Anne;Konrath, Sandra;Papareddy, Praveen;Butler, Lynn M.;Stavrou, Evi X.;Frye, Maike;Gelderblom, Mathias;Nieswandt, Bernhard;Hammerschmidt, Sven;Herwald, Heiko;Renné, Thomas
doi: 10.1084/jem.20250049pmid: 40261297
Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)–triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12−/−) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12−/− mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12−/− mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.
Oligodendrocyte-derived IL-33 regulates self-reactive CD8+ T cells in CNS autoimmunityFonta, Nicolas;Page, Nicolas;Klimek, Bogna;Piccinno, Margot; Di Liberto, Giovanni;Lemeille, Sylvain;Kreutzfeldt, Mario;Kastner, Anna Lena;Ertuna, Yusuf I.;Vincenti, Ilena;Wagner, Ingrid;Pinschewer, Daniel D.;Merkler, Doron
doi: 10.1084/jem.20241188pmid: 40227193
In chronic inflammatory disorders of the central nervous system (CNS), tissue-resident self-reactive T cells perpetuate disease. The specific tissue factors governing the persistence and continuous differentiation of these cells remain undefined but could represent attractive therapeutic targets. In a model of chronic CNS autoimmunity, we find that oligodendrocyte-derived IL-33, an alarmin, is key for locally regulating the pathogenicity of self-reactive CD8+ T cells. The selective ablation of IL-33 from neo–self-antigen–expressing oligodendrocytes mitigates CNS disease. In this context, fewer self-reactive CD8+ T cells persist in the inflamed CNS, and the remaining cells are impaired in generating TCF-1low effector cells. Importantly, interventional IL-33 blockade by locally administered somatic gene therapy reduces T cell infiltrates and improves the disease course. Our study identifies oligodendrocyte-derived IL-33 as a druggable tissue factor regulating the differentiation and survival of self-reactive CD8+ T cells in the inflamed CNS. This finding introduces tissue factors as a novel category of immune targets for treating chronic CNS autoimmune diseases.