Kelchtermans L, Geerts K, Pham CT
… +8 more, Malviya V, Chiu W, De Keyzer C, Broeckhoven E, Neyts J, Schlenner S, Alpizar YA, Dallmeier K
Nat Immunol
· 2026 Jun · PMID 41882206
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Recurring outbreaks of filoviruses, including Ebola virus and Sudan virus, threaten to cause large epidemics. No treatment or vaccine is available for Sudan virus and how protective immunity is achieved remains unknown....Recurring outbreaks of filoviruses, including Ebola virus and Sudan virus, threaten to cause large epidemics. No treatment or vaccine is available for Sudan virus and how protective immunity is achieved remains unknown. To unravel mechanisms contributing to protection, we used a surrogate mouse model of Sudan virus infection amenable to deep functional analysis. Mice vaccinated with a live viral vector based on live-attenuated YF17D expressing Sudan virus glycoprotein were protected against lethal challenge with a surrogate virus, a chimeric recombinant vesicular stomatitis virus expressing Sudan virus glycoprotein, despite lacking virus-neutralizing antibodies. Glycoprotein-specific humoral responses associated with antibody-mediated neutrophil phagocytosis and natural killer cell activation suggested Fcγ receptor (FcγR) effector involvement. However, protection was not compromised in FcγR-deficient mice. By contrast, targeted depletion and reconstitution experiments identified antigen-experienced interferon-γ (IFNγ)-secreting CD4 T cells, particularly short-lived effector cells and regulatory T cells as key players for survival. Multiple complementary vaccination-induced effector mechanisms may contribute to Sudan virus immunity; however, only proliferative antigen-specific CD4 T cells and sustained IFNγ production, orchestrating an acute antiviral response, appear required for protection.
Chhatbar C, Sankowski R, Schulz M
… +52 more, Shimizu T, Schwabenland M, Staszewski O, Scheiwe C, Nessler S, Borst K, Dumas AA, Trost E, Berchtold D, Brandão W, Mossad O, Dalmau Gasull A, Frosch M, Erny D, Diebold M, Guffart E, Ternka K, Guranda M, Vinnakota JM, Friesen M, Ouk K, Waltl I, LaMorte M, Hammond TR, Di Liberto G, Vincenti I, Kreutzfeldt M, Mughrabi IT, Al-Abed Y, Blank T, Meyer-Luehmann M, Crow YJ, Hagen N, Ofengeim D, Zeiser R, Kettwig M, Gärtner J, Meisel A, Schwemmle M, Kalinke U, Beck J, Bengsch B, Thimme R, Butovsky O, Seredenina T, Ransohoff RM, Quintana FJ, Kierdorf K, Merkler D, Stadelmann C, Priller J, Prinz M
Nat Immunol
· 2026 May · PMID 41882205
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Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states across contexts is needed. Here...Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states across contexts is needed. Here we generated an atlas of myeloid cell states by single-cell RNA sequencing more than one million central nervous system cells from more than 30 physiological and pathological conditions. This atlas enables us to establish a comprehensive taxonomy of myeloid cell states across brain disorders and related mouse models, comprising 27 superclusters and 192 clusters that are prevalent across diseases and largely conserved. We augment this taxonomic framework with spatial transcriptomics to map how immune cell states are organized within tissue and interact with their local cellular environment. Using in vivo perturbations, we also show that activation-associated microglial states are dependent on interferon and colony-stimulating factor 1 receptor signaling. Together, these findings provide a spatially aware taxonomic framework for central nervous system immune cells in health and disease.
Fujiwara H, Seike K, Brooks MD
… +18 more, Mathew AV, Kovalenko I, Pal A, Lee HJ, Peltier D, Kim S, Liu C, Oravecz-Wilson K, Li L, Sun Y, Byun J, Maeda Y, Wicha MS, Saunders TL, Rehemtulla A, Lyssiotis CA, Pennathur S, Reddy P
Lauder E, Gondal M, Wu MC
… +7 more, Yamamoto A, Maneix L, Zhao D, Sun Y, Cieslik M, Chinnaiyan AM, Reddy P
Nat Immunol
· 2026 May · PMID 41876718
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Major histocompatibility complex (MHC) class I and class II molecules present antigens to CD8 and CD4 T cells respectively. Here we uncover a previously unrecognized role for MHC class I in modulating CD4 T cell-mediated...Major histocompatibility complex (MHC) class I and class II molecules present antigens to CD8 and CD4 T cells respectively. Here we uncover a previously unrecognized role for MHC class I in modulating CD4 T cell-mediated immunity. In allogeneic graft-versus-host disease and tumor models, we demonstrate that the absence of MHC class I on target cells significantly increases their susceptibility to CD4 T cell cytotoxicity. Transcriptomic and functional studies suggest that this was because of heightened sensitivity to enhanced ferroptosis of the target cells. In large human transcriptomic and sequencing datasets, a role for CD4 T cells in enhancing immune checkpoint blocker-mediated responses in persons with melanoma and mismatch-repair-deficient colon cancers that have downregulated MHC class I was suggested. These findings revise and expand the known role of MHC class I in CD8 T cell and natural killer cell immunity and demonstrate a previously unrecognized role in CD4 T cell-mediated cancer and alloimmunity.
Excessive activation of interleukin-17-producing helper T (T17) cells can cause autoimmune tissue inflammation. However, how T17 cells enhance their pathogenicity within target tissues and whether destabilized regulatory...Excessive activation of interleukin-17-producing helper T (T17) cells can cause autoimmune tissue inflammation. However, how T17 cells enhance their pathogenicity within target tissues and whether destabilized regulatory T cells contribute to pathogenic T17 cell populations remain unclear. Using a T17 cell-dependent autoimmune arthritis model, we demonstrated that T17 and regulatory T cells did not undergo significant mutual plasticity, based on lineage-tracing and T cell receptor (TCR) repertoire analyses. Single-cell RNA sequencing of joint CD4 T cells revealed three phenotypically distinct T17 clusters, ranging from a CD103⁺ Tcf1 stem-like state to a CD200⁺ Egr2 highly pathogenic state. The phenotypic transition to the CD200⁺ pathogenic state was not a default progression driven by inflammatory cues, but rather a highly selective process mediated by tissue-restricted secondary TCR engagement within inflamed joints. Our findings delineate the heterogeneity and pathogenic potential of arthritogenic T17 cells, highlighting secondary autoimmune TCR signaling as a critical regulatory determinant of their developmental trajectories that may serve as a therapeutic target for autoimmune arthritis.
Kim YM, Tsai MK, Sun C
… +4 more, Laveroni O, Akana RV, Frombach K, Jerby L
Nat Immunol
· 2026 May · PMID 41872506
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Natural killer (NK) cells and T cells need to infiltrate solid tumors to eradicate them. Here we show programmable mechanisms that can mobilize NK and T cells to solid tumors using metabolite-sensing receptors. In vivo a...Natural killer (NK) cells and T cells need to infiltrate solid tumors to eradicate them. Here we show programmable mechanisms that can mobilize NK and T cells to solid tumors using metabolite-sensing receptors. In vivo and in vitro CRISPR activation screens using NK-92 cells identified GPR183, GPR84, GPR34 and GPR18 as top enhancers of infiltration and chemotaxis to breast and ovarian cancers. While endogenously expressed in restricted cellular contexts, expressing these receptors in NK and T cells drives migration to factors released by cancer cells and alters the NK cell transcriptome in a ligand-dependent manner. Expressing GPR183 in NK, chimeric antigen receptor (CAR) NK and CAR T cells increased tumor infiltration and control. Likewise, expressing GPR183 in mouse T cells increased tumor eradication in immunocompetent mice. These data show that metabolite sensing can be rewired to obtain biochemically guided spatially targeted cells, creating new possibilities for therapeutic intervention.
Ghosh S, Li X, Rawat K
… +6 more, Dighal A, Kalinowski S, Hosseini R, Kolling FW, Ringelberg CS, Jakubzick CV
Nat Immunol
· 2026 Apr · PMID 41872505
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Macrophages are among the most abundant immune cells in solid tumors, yet how macrophage lineage and spatial organization shape antitumor immunity remains unclear. Here we uncovered a division of labor between tissue-res...Macrophages are among the most abundant immune cells in solid tumors, yet how macrophage lineage and spatial organization shape antitumor immunity remains unclear. Here we uncovered a division of labor between tissue-resident CD206 and CD206 interstitial macrophage (IM) subsets and Ly6c2Fn1Vcan recruited macrophages (recMacs) in lung cancer. Using single-cell and spatial transcriptomics, we identified chemokine-expressing IM subsets with opposing functions. Cxcl13CD206 IMs, Cxcl9CD206 IMs and Cxcl10CD206 IMs positioned along bronchovascular regions drove tertiary lymphoid structure formation, lymphocyte recruitment and tumor control, whereas Ccl2 IMs, localized within tumor regions, recruited protumorigenic Ly6c2Fn1Vcan recMacs. In addition, Ly6CCD11b monocyte-derived dendritic cells (moDCs) functioned as immunosuppressive antigen-presenting cells in tumor-draining lymph nodes. During neoantigen vaccination, CCR5 blockade with maraviroc selectively inhibited antigen-bearing moDC migration, enhancing dendritic cell-mediated antitumor immunity. These findings showed how macrophage lineage and spatial compartmentalization govern tumor immunity and identified strategies to preserve protective IM functions, while disrupting macrophage-driven immunosuppression.
Ghneim K, Ten-Caten F, Santana AC
… +30 more, Latif MB, Diaz-Dinamarca DA, García-Salum T, Del Rio Estrada PM, Sohal P, Strongin Z, Harper J, Jean S, Wallace C, Balderas R, Lifson JD, Raghunathan G, Rimmer E, Pastuskovas CV, Wu G, Micci L, Martins Sieben LF, Lopes Gerum PC, Dos Santos J, Netea MG, van der Ven A, Silvestri G, Hazuda DJ, Gorman DM, Howell BJ, Sharma AA, Paiardini M, Soudeyns H, Pereira Ribeiro S, Sekaly RP
Nat Immunol
· 2026 Apr · PMID 41862649
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Immune interventions toward an HIV cure have focused on rejuvenating adaptive immune responses. Herein we provide a framework that features epigenetic programming of myeloid and CD4 T cells as a major mechanism that prom...Immune interventions toward an HIV cure have focused on rejuvenating adaptive immune responses. Herein we provide a framework that features epigenetic programming of myeloid and CD4 T cells as a major mechanism that promotes decay of the HIV reservoir. Coordinate regulation of gene expression and chromatin accessibility of pathways of innate antiviral immunity was associated with decay of cell-associated viral DNA (CA-vDNA) following analytical treatment interruption in simian immunodeficiency virus-infected rhesus macaques (RMs) treated with anti-IL-10 and anti-PD-1. TGF-β/SMAD signaling in a subset of combo-treated CA-vDNA RMs, suppressed this antiviral activity through histone deacetylases, reducing chromatin accessibility of interferon regulatory factors (IRFs) and STATs. Addition of HDAC inhibitors in vitro restored antiviral response in the presence of TGF-β. Induction of IL-6 in CA-vDNA RMs amplified the antiviral network through IRF9. We identified an overlapping molecular cascade in HIV elite controllers, who maintain small HIV reservoirs without antiviral treatment. These data provide insights into strategies for HIV cure interventions.
Khurana S, Posadas O, Kardava L
… +13 more, Coyle EM, Ravichandran S, Grubbs G, McConnell R, Rouphael N, Poliquin G, Langley JM, Chu E, Follmann DA, Shang X, Li Y, Moir S, Davey RT
Nat Immunol
· 2026 May · PMID 41857394
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Short-term boosting of the currently licensed rVSV∆G-ZEBOV-GP vaccine does not generate lasting antibody respones to Ebola virus (EBOV), prompting interest in strategies that elicit more durable immunity. Here, we elucid...Short-term boosting of the currently licensed rVSV∆G-ZEBOV-GP vaccine does not generate lasting antibody respones to Ebola virus (EBOV), prompting interest in strategies that elicit more durable immunity. Here, we elucidated the longitudinal humoral immune repertoire over 3 years following prime and boost rVSV∆G-ZEBOV-GP vaccinations administered 18 months apart in healthy adults compared to participants randomized to no boost. This delayed booster vaccination induced long-lasting EBOV-neutralizing antibodies that persisted up to 36 month at levels similar to peak titers after a single dose. Phage display libraries, expressing linear and conformational epitopes of EBOV glycoprotein (GP), demonstrated a highly diverse and durable antibody epitope repertoire following prime boost vaccination. Delayed booster vaccination recalled memory B cells, promoted anti-GP IgG class switching and induced antibodies specific to GP with Fcγ receptor interaction and functional antibody-dependent cellular cytotoxicity and phagocytosis. The 18-month interval led to 13-fold higher antibody affinity maturation than a single dose, maintained up to 36 months. Overall, delayed rVSV∆G-ZEBOV-GP booster vaccination promoted a diverse, stronger, durable, predominant IgG, highly affinity-matured antibody response to GP.
Fliegauf M, Levard D, Cardamone F
… +22 more, Frosch M, Kuhn S, Sankowski R, Provinciali M, Dumas AA, Dalmau Gasull A, Aktories P, Oschwald A, Schwabenland M, Scholz R, Beyer MD, Neher JJ, Kollefrath M, Baltas D, Reichardt W, von Elverfeldt D, Vivien D, Cupovic J, Iovino N, Rubio M, Amann L, Prinz M
Nat Immunol
· 2026 May · PMID 41851525
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Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and...Nonparenchymal central nervous system (CNS)-associated macrophages (CAMs) mediate immune responses at brain boundaries. Perivascular and leptomeningeal CAMs are collectively termed subdural CAMs (sdCAMs). Both sdCAMs and juxtaneuronal microglia are derived from embryonic yolk sac precursors, long-living and maintain their populations through self-renewal. Following depletion, microglia autonomously repopulate from single surviving cells. In contrast, the course of sdCAM repopulation remains poorly understood. Here, by combining multilineage fate mapping, multiomic profiling and high-resolution imaging, we demonstrate divergent repopulation dynamics between sdCAMs and microglia. Unlike microglia, sdCAMs do not renew cell-autonomously, but become transiently accessible to CCR2Ly6C monocyte engraftment after niche induction in an integrin-dependent manner. Moreover, replenished monocyte-derived sdCAMs remain transcriptomically, epigenetically and functionally distinct from their embryo-derived counterparts. Finally, we present a protocol enabling selective exchange of sdCAMs, modulating disease response without functionally affecting microglia. These new insights into CNS immune biology suggest new therapeutic avenues for neuroinflammatory and neurodegenerative diseases.
Park YH, Batu ED, Matthiasardottir B
… +4 more, Kim Y, Akkaya-Ulum YZ, Kastner DL, Chae JJ
Nat Immunol
· 2026 May · PMID 41851524
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Mutations in NLRP3 can cause a spectrum of the autoinflammatory cryopyrin-associated periodic syndromes (CAPS). Reactive oxygen species (ROS) have a central role in NLRP3 inflammasome activation. Here we show that cofili...Mutations in NLRP3 can cause a spectrum of the autoinflammatory cryopyrin-associated periodic syndromes (CAPS). Reactive oxygen species (ROS) have a central role in NLRP3 inflammasome activation. Here we show that cofilin-1, an actin-severing protein, is a negative regulator of the NLRP3 inflammasome. In resting cells, cofilin-1 directly bound NLRP3, but after stimulation with NLRP3 inflammasome activators, it was oxidized by ROS and dissociated from NLRP3. CAPS-associated mutant NLRP3 exhibited reduced binding to cofilin-1. Residues 101-104 of cofilin-1 were critical for NLRP3 interaction. Oxidation-independent peptides containing this NLRP3 binding motif suppressed inflammasome activation induced by endogenous CAPS-associated mutations and ex vivo NLRP3 activators such as ATP and nigericin. Bioinformatic structural analyses corroborate a model in which cofilin-1 has a pivotal function in NLRP3 activation by ROS and support the potential use of cofilin-1-derived peptides in individuals who are unresponsive to or intolerant of other forms of NLRP3 blockade.
Natural killer (NK) cells are innate immune effectors, but their cytotoxic potential can be compromised within the immunosuppressive tumor microenvironment. Identifying molecular mechanisms that underly this dysfunction...Natural killer (NK) cells are innate immune effectors, but their cytotoxic potential can be compromised within the immunosuppressive tumor microenvironment. Identifying molecular mechanisms that underly this dysfunction is essential for advances in cancer immunotherapy. Here we show that CLEC12B, a C-type lectin receptor, functions as an inhibitory checkpoint that restricts NK cell-mediated antitumor immunity. High expression of CLEC12B by tumor-infiltrating NK cells correlates with poor clinical prognosis in patients with hepatocellular carcinoma. We identify lipoprotein lipase as a functional ligand for CLEC12B, triggering inhibitory signaling that suppresses NK cell activation. We developed a high-affinity nanobody as a potential therapeutic that disrupts the CLEC12B-lipoprotein lipase axis, thereby revitalizing NK cell activity and suppressing tumor progression in preclinical models. Furthermore, this nanobody has potent synergistic efficacy when combined with PD-1 blockade. These findings establish CLEC12B as a promising therapeutic target for rearming the immune system against solid malignancies.
Jeltsch KM, Hu D, Brenner S
… +25 more, Zöller J, Heinz GA, Nagel D, Vogel KU, Rehage N, Warth SC, Edelmann SL, Gloury R, Martin N, Lohs C, Lech M, Stehklein JE, Geerlof A, Kremmer E, Weber A, Anders HJ, Schmitz I, Schmidt-Supprian M, Fu M, Holtmann H, Krappmann D, Ruland J, Kallies A, Heikenwalder M, Heissmeyer V