Relano-Rodriguez I, Du J, Lin ZJ
… +25 more, Kerwin M, Tarquis-Medina M, Urbano E, Cui J, Watkins M, Lavine CL, Zhao P, Habib R, Agostino C, Ghosh S, Park J, Boroughs C, Walsh AA, Melo MB, Shukla N, Shaw GM, Hahn BH, Irvine DJ, Wells L, Weiner DB, Seaman MS, Kulp DW, Veazey RS, Pallesen J, Escolano A
Nat Immunol
· 2026 Mar · PMID 41634485
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Sequential immunization is a promising approach to elicit broadly neutralizing antibodies (bNAbs) against the HIV-1 Envelope (Env). However, available protocols are inefficient and involve multiple immunizations over lon...Sequential immunization is a promising approach to elicit broadly neutralizing antibodies (bNAbs) against the HIV-1 Envelope (Env). However, available protocols are inefficient and involve multiple immunizations over long periods of time. Here, we present WIN332, a new engineered Env immunogen that induces a new class of Asn332-glycan-independent antibodies to the conserved V3-glycan epitope of Env with low inhibitory activity indicative of a neutralization activity after a single bolus immunization in nonhuman primates. WIN332 binds to precursors of canonical human Asn332-glycan-dependent (type-I) V3-glycan bNAbs but also of a first-of-its-class Asn332-glycan-independent (type-II) V3-glycan bNAb. A single immunization elicits low inhibitory serum and monoclonal antibodies that are boosted and affinity matured with a heterologous immunogen. Electron microscopy polyclonal epitope mapping analysis of serum antibodies, antibody cloning and cryogenic electron microscopy analysis reveals that WIN332 elicits Asn332-glycan-independent antibodies with striking sequence and binding similarities with the most potent human type-I and type-II V3-glycan bNAbs. Thus, WIN332 is a promising vaccine candidate to streamline V3-glycan bNAb elicitation.
Naouar I, Pangan A, Zuo M
… +19 more, Raza SA, Champagne-Jorgensen K, Patel J, Wang A, Pu A, Ward L, Ahn JSY, Sayeed FN, Zhu J, Pössnecker E, Spring S, Sled JG, Cenni B, Nuesslein-Hildesheim B, Browning JL, Pröbstel AK, Reich DS, Gommerman JL, Ramaglia V
Le S, Dooley N, Murphy D
… +23 more, Liu S, Gandolfo LC, Ge Z, May R, Cozijnsen A, Burn TN, Jennison C, Bachem A, Xu C, Koay HF, Schröder J, Oyong D, Nalubega M, Kenangalem E, Gras S, Cockburn IA, Bedoui S, Mackay LK, McFadden GI, Fernandez-Ruiz D, Boyle M, Heath WR, Beattie L
Nat Immunol
· 2026 Feb · PMID 41617969
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Dendritic cells (DCs) are pivotal for initiating adaptive immunity, a process triggered by the activation of DCs via pathogen products or damage. Immunization with sporozoites from Plasmodium leads to CD8 T cell priming...Dendritic cells (DCs) are pivotal for initiating adaptive immunity, a process triggered by the activation of DCs via pathogen products or damage. Immunization with sporozoites from Plasmodium leads to CD8 T cell priming in a response initiated by collaboration between conventional type 1 DCs (cDC1s) and γδ T cells. Here we show that Vγ1 γδ T cells have an initiating role by directly supplying interleukin-4 (IL-4). IL-4 and interferon-γ (IFNγ) synergize with CD4 T cell-derived CD40L to induce IL-12 production by cDC1. Both IL-12 and IL-4 then directly signal responding CD8 T cells and drive enhanced IL-12 receptor expression and expansion. This study shows how Vγ1 γδ T cells can initiate CD8 T cell immunity to Plasmodium and that responses to some pathogens require help from innate-like T cells to pass an initiation threshold and further amplify the response in a process underscored by IL-4 production.
Hamaidi I, Cheng P, Jun SY
… +18 more, Manna A, Wang MH, Nguyen A, Can I, Zhang MG, Taylor OO, Bailon LUL, Fang B, Perez B, Creelan BC, Marusyk A, Shin D, Hwang TH, Berglund AE, Shapiro VS, Ji HM, Conejo-Garcia JR, Kim S
Nat Immunol
· 2026 Feb · PMID 41611868
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T cell receptor (TCR) signaling is precisely tuned to prevent self-reactivity while allowing protective immunity. Here we found that acetylation modulated TCR signaling. The loss of SIRT2 deacetylase activity in T cells...T cell receptor (TCR) signaling is precisely tuned to prevent self-reactivity while allowing protective immunity. Here we found that acetylation modulated TCR signaling. The loss of SIRT2 deacetylase activity in T cells led to amplified calcium mobilization and phosphorylation of key proximal TCR molecules in naive T cells and reversed dampened TCR signaling in anergic T cells. During thymic selection, SIRT2 deficiency lowered the TCR signaling threshold and resulted in a broader TCR repertoire diversity. Mechanistically, we identified acetyl-lysine K228 on the linker region of LCK as a substrate specific for SIRT2 that governed LCK conformation and activity. SIRT2 inhibition in exhausted mouse and human tumor-infiltrating T cells restored TCR responsiveness and antitumor immunity. These findings highlighted SIRT2-modulated protein acetylation as a regulatory mechanism that set the TCR threshold in T cells.
Chen HH, Tyystjärvi S, Ruiz Navarro D
… +19 more, Kant R, Groll T, Wagner I, Domínguez Moreno H, Bonafonte-Pardàs I, Öllinger R, Afzali AM, Heink S, Richter LC, Sie C, Lepennetier G, Seeholzer L, Steiger K, Merkler D, Rad R, Schotta G, Schubert B, Muschaweckh A, Korn T
Nat Immunol
· 2026 Mar · PMID 41611867
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Foxp3-expressing regulatory T (T) cells protect against systemic autoimmunity. However, little is known about the significance of T cells in inflammation-experienced tissues. Here, we use an experimental autoimmune encep...Foxp3-expressing regulatory T (T) cells protect against systemic autoimmunity. However, little is known about the significance of T cells in inflammation-experienced tissues. Here, we use an experimental autoimmune encephalomyelitis model and show that T cells accumulate and persist in the central nervous system (CNS) long after the resolution of the bulk of the inflammatory infiltrate. CNS-specific depletion of postinflammatory T cells, but not systemic depletion of T cells, results in autoimmune inflammatory flares in the CNS by residual local effector T cells. Expression of the NAD-consuming ectoenzyme CD38 is crucial for the functional adaptation of postinflammatory CNS T cells to a stressful microenvironment, in which access to interleukin-2 (IL-2) is limited. CD38 counteracts ADP-ribosylation of the IL-2 receptor and thus maintains its high sensitivity to IL-2. This fully functional high-affinity IL-2 receptor prevents the loss of tissue-resident antigen-specific T cells. These 'stress-tolerant' CNS T cells impede the collapse of immune homeostasis in the CNS once acute inflammation is controlled.
Guivarch M, Meyer P, Braud A
… +17 more, Marschall P, Perrin A, Verdenet A, Vu Manh TP, Santa P, Sisirak V, Zhang YL, Flatter E, Ye T, Jung M, Birling MC, Hener P, Segaud J, German B, Lipsker D, Dalod M, Li M
Thymic stromal lymphopoietin (TSLP), initially described as a driver of type 2 helper T cell responses, can also act on dendritic cells (DCs) to promote the generation and accumulation of GATA3-expressing effector regula...Thymic stromal lymphopoietin (TSLP), initially described as a driver of type 2 helper T cell responses, can also act on dendritic cells (DCs) to promote the generation and accumulation of GATA3-expressing effector regulatory T (eT) cells in the context of cutaneous melanoma. In this study, using an experimental mouse model with induced TSLP expression by epidermal keratinocytes combined with genetic tools, we find that TSLP drives GATA3 eT cells through a specific migratory DC population where the co-stimulatory molecule OX40L is required. By conducting transcriptomic identity, lineage-traced ontogeny, surface marker expression and functional studies, we identified and characterized this DC population. Our data demonstrated that TSLP acts on transitional dendritic cell-derived DC2 to promote GATA3 eT cells, thus uncovering a previously unrecognized tolerogenic axis in promoting immunosuppression, which is likely conserved in humans, across contexts of inflammation and cancer.
Hobson R, Levy SHS, Singal CMS
… +10 more, Flaherty D, Xiao H, Ciener B, Reddy H, Zabinyakov N, Kim CY, Teich AF, Shneider NA, Bradshaw EM, Elyaman W
Nat Immunol
· 2026 Feb · PMID 41593242
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Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegene...Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. Here we performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer's disease (AD), amyotrophic lateral sclerosis and Parkinson's disease and found that although the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (T) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally, in AD, the degree of CD8 T clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.
Mulder K, Gardet M, Kong WT
… +28 more, Patel AA, Calvez A, Gessain G, de la Calle-Fabregat C, Piot C, Blampey Q, Poupaud E, Anzali AA, Dunsmore G, Bougouin A, Pupier G, He L, Wiggins T, He J, Emanuel G, Goubet AG, Al-Eryani G, Swarbrick A, Michels J, Dress RJ, Deloger M, Bertoletti A, Thomas de Montpreville V, Sautès-Fridman C, Fridman WH, Zitvogel L, Ginhoux F, Dutertre CA
van Haften FJ, van der Sluis TC, Hepp HS
… +25 more, Mülling N, Nadafi R, Sampadi B, van Duikeren S, Mostert JS, van der Sterre R, van Veelen PA, Heieis GA, Veerkamp DMB, Wesselink TH, Vleeshouwers W, Beijnes M, Pardieck IN, van Horssen ELF, de Groot AF, van der Ploeg M, Kroep JR, de Miranda NFCC, van der Zanden SY, Neefjes J, Mei H, Vertegaal ACO, Everts B, van der Burg SH, Arens R
Nat Immunol
· 2026 Mar · PMID 41555086
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Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8 T cells that undergo...Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8 T cells that undergo synchronized proliferation and differentiation. How CD8 T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8 T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8 T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8 T cells following arrest. Transient arrest in vivo enables superior CD8 T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8 T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.
Shinzawa M, Ramos N, Bui K
… +6 more, Hajjar W, Crossman A, Chen X, Cam M, Takahama Y, Singer A
Nat Immunol
· 2026 Apr · PMID 41555085
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Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8...Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8 co-receptors in both Cd4 and Cd8 gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8 T cell subsets. Strikingly, such mice revealed that functionally different CD8 T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by β5t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8 T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by nonβ5t-peptides expressed throughout the thymus become either helper or innate memory CD8 T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8 T cells, integrating peptide specificity and CD8 T cell function during positive selection and thymocyte migration.