Stadinski BD, Mills EA, Humphries PA
… +13 more, Cleveland SB, Dow P, Murakami K, Li YR, Murakami M, Ono M, Au-Yeung BB, Morris GP, Zúñiga-Pflücker JC, Campbell RA, Griffiths ER, Huseby ES, Lo WL
Nat Immunol
· 2026 Apr · PMID 41714739
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Ogawa C, Okuyama K, Kojo S
… +15 more, Nishino K, Machiyama H, Padhi AK, Takahashi H, Ebihara T, Tenno M, Zhizhen Q, Muroi S, Ito K, Sawasaki T, Zhang KYJ, Xue HH, Yokosuka T, Kosako H, Taniuchi I
Nat Immunol
· 2026 Apr · PMID 41714737
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MHC-I- and MHC-II-selected CD4CD8 precursor thymocytes differentiate into cytotoxic CD8 and helper CD4 lineage T cells, during which suppression of Cd4 and Thpok genes by Runx-dependent-silencers in those genes is crucia...MHC-I- and MHC-II-selected CD4CD8 precursor thymocytes differentiate into cytotoxic CD8 and helper CD4 lineage T cells, during which suppression of Cd4 and Thpok genes by Runx-dependent-silencers in those genes is crucial to segregate the two lineages. However, how TCR signals are linked to cytotoxic-lineage-specific Cd4-Thpok silencing remains unclear. Here we show that the terminal Y residue within the evolutionarily conserved C-terminal WRPY motif in Runx1, which is essential for interacting with TLE co-repressor proteins, was phosphorylated more in CD4CD8 thymocytes than in CD4CD8 thymocytes, inducing an interaction with TLE co-repressors for cytotoxic-lineage specific Cd4-Thpok silencing. Non-receptor tyrosine kinases Lck and Zap70 interacted with Runx in the cytoplasm more in MHC-I-signaled CD4CD8 thymocytes than in CD4CD8 thymocytes. Collectively, these findings reveal that differential phosphorylation states at the terminal tyrosine residue in Runx connect MHC restriction with the helper versus cytotoxic T cell lineage choice.
Hanemaaijer ES, Müskens KF, Kal IJ
… +13 more, Chen LT, Te Pas BM, Fryzik P, Epskamp N, van der Meulen M, Balwierz AK, Saikumar Jayalatha AK, Scheijde-Vermeulen M, Heidenreich O, Candelli T, de Jonge WJ, Margaritis T, Belderbos ME
Nat Immunol
· 2026 Mar · PMID 41703319
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Childhood is a critical period for hematopoietic development and susceptibility to hematologic disease. Here we generated a multimodal single-cell atlas of healthy human bone marrow, capturing mRNA and surface protein ex...Childhood is a critical period for hematopoietic development and susceptibility to hematologic disease. Here we generated a multimodal single-cell atlas of healthy human bone marrow, capturing mRNA and surface protein expression in 90,710 cells, including over 20,000 hematopoietic stem and progenitor cells (HSPC) and mesenchymal stromal cells (MSC) from nine donors ranging from infancy to young adulthood (2-32 years). Young pediatric (YP) bone marrow (<10 years) was compositionally and molecularly distinct from adolescent and young adult (AYA) bone marrow (≥13 years), with hematopoietic output shifting from B cell dominance in YP bone marrow to myeloid and T cell bias in AYA bone marrow. Spatial transcriptomics of six bone marrow biopsies (0-23 years) confirmed these age-dependent changes. Two lymphoid progenitor (LyP) subsets regulated this lineage shift: CD127 LyP cells with B cell-biased output were enriched before age 10, whereas CD127 LyP cells with combined lymphoid and myeloid features predominated thereafter. Stromal signaling showed corresponding age-dependent changes, with increased interleukin-7 production by bone marrow MSC in YP compared to AYA, indicating niche-mediated regulation of HSPC lineage potential during ontogeny. This single-cell atlas provides a comprehensive resource for understanding hematopoietic development and early-life origins of hematologic disease.
Olin A, Pou C, Jaquaniello A
… +21 more, Crook J, Tan Z, Roux M, Dubois F, Charbit B, Liu D, Donnadieu F, Garcia L, Lambert C, Bloch E, Clave E, Araujo IL, Toubert A, Rotival M, Simon-Lorière E, White M, Brodin P, Duffy D, Quintana-Murci L, Patin E, Milieu Intérieur Consortium
Nat Immunol
· 2026 Mar · PMID 41699059
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Antibodies are central to immune defenses. Despite advances in understanding the mechanisms of antibody generation, a comprehensive model of how intrinsic and external factors shape human humoral responses to viruses has...Antibodies are central to immune defenses. Despite advances in understanding the mechanisms of antibody generation, a comprehensive model of how intrinsic and external factors shape human humoral responses to viruses has been lacking. Here we apply phage immunoprecipitation sequencing to investigate the effects of demographic factors-including 108 lifestyle and health-related variables-and genetic variation on antibody reactivity to over 97,000 viral peptides in 1,212 healthy adults. We demonstrate that age, sex and continent of birth extensively affect not only the viruses but also the specific viral epitopes targeted by the antibody repertoire. Notably, we find that antibodies against rapidly evolving epitopes of influenza A virus decrease with age, whereas immunoreactivity to conserved epitopes increases. Furthermore, we identify strong associations between antibodies against 34 viruses and genetic variants at HLA, FUT2, IGH and IGK loci, some of which increase autoimmune disease risk. These findings offer a valuable resource for understanding the factors affecting antibody-mediated immunity, laying the groundwork for optimizing vaccine strategies.
Lai J, Chan CW, Armitage JD
… +27 more, Audsley KM, Huang YK, Derrick EB, Carstensen LS, Scheffler CM, Jones ME, Sek K, Principe N, Kim JS, House IG, Chen AXY, Yap KM, Middelburg J, Munoz I, Nguyen D, Tong J, Hoang TX, Todd KL, Evrard M, Chee J, Mackay LK, Forrest ARR, Parish IA, Bosco A, Waithman J, Beavis PA, Darcy PK
Nat Immunol
· 2026 Mar · PMID 41667622
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Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to pr...Immune checkpoint blockade (ICB) evokes antitumor immunity through the reinvigoration of T cell responses. T cell differentiation status controls response, with less differentiated cells having an enhanced capacity to proliferate after ICB. Given that conventional type 1 dendritic cells (cDC1) maintain precursor exhausted T cells (T), we hypothesized that expansion of cDC1s with Flt3L could enhance responses to ICB. Here we show that treatment with Fms-related tyrosine kinase 3 ligand (Flt3L) expands CD62LSLAMF6CD8 T cells in the tumor through a mechanism that requires XCR1 dendritic cells to traffic to the tumor-draining lymph node. The combination of Flt3L and anti-CTLA-4 enhanced therapeutic responses. Combination therapy is associated with the emergence of a CD8 T cell subset characterized by the expression of Il21r and oligoclonal expansion of CD8 T cells within tumors through a mechanism that is dependent on lymph node egress.
Alharbi AS, Sapkota S, Zhang Z
… +30 more, Jin R, Rupasinghe E, Jayasekara WSN, Yu D, Speir M, Wilkinson-White L, Cubeddu L, Ellyard JI, Rezwan R, Wenholz DS, McAllan AL, Gao R, Ying L, Sathiqu RM, Hosseini Far H, Bones J, He S, Alexander MR, Lennox KA, Hertzog PJ, Nold-Petry CA, Stewart CR, Vinuesa CG, Behlke MA, Ohto U, Laczka OF, Gamsjaeger R, Corry B, Shimizu T, Gantier MP
Nat Immunol
· 2026 Apr · PMID 41667621
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Recognition of RNA fragments by Toll-like receptor 7 (TLR7) and TLR8 helps to initiate the innate immune response against pathogens. An outstanding question is why RNA fragments generated during clearance of apoptotic ce...Recognition of RNA fragments by Toll-like receptor 7 (TLR7) and TLR8 helps to initiate the innate immune response against pathogens. An outstanding question is why RNA fragments generated during clearance of apoptotic cells fail to activate TLR7 and TLR8 signaling. Here we show that select 2'-O-methyl (2'-OMe) guanosine RNA fragments, including those derived from host RNAs, function as potent TLR7 and TLR8 antagonists and reduce TLR7 sensing in vivo. Mechanistically, these fragments bind to an antagonistic site on these proteins via their 5'-end 2'-OMe guanosine. These findings indicate that host RNAs evade detection because abundant ribosomal 2'-OMe-modified fragments naturally antagonize TLR7 and TLR8. Crucially, rare TLR7 and TLR8 mutations at this antagonist binding site decrease inhibition by 2'-OMe guanosine RNA fragments, leading to autoimmunity in patients. Collectively, this work redefines TLR7 and TLR8 sensing by introducing 2'-OMe guanosine as a natural immune checkpoint for their activation.
Memory CD8 T (T) cells are activated into innate-like killers by cytokines, including interleukin-12 (IL-12), IL-15 and IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are unclear. Here we...Memory CD8 T (T) cells are activated into innate-like killers by cytokines, including interleukin-12 (IL-12), IL-15 and IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are unclear. Here we show that basal IL-4 signals antagonize IL-18 sensing and subsequent interferon-γ production during T cell bystander activation. IL-4 treatment can act directly on T cells in a STAT6-dependent manner to limit interferon-γ-mediated control of a bystander bacterial infection. IL-4 does not simply block bystander activation but tunes effector molecule expression. Strain-specific defects in bystander activation of homeostatic T cells partially relates to IL-4 exposure, but these differences are erased in T cells produced by T cell antigen receptor activation, leading to uniform IL-18 receptor expression and capacity for bystander activation/cytotoxicity. Our data demonstrate that bystander activation by inflammatory cytokines is subject to regulation by both IL-4 and prior antigen experience. These findings underscore the importance of the cytokine milieu in dictating bystander-mediated pathogen control.
Theofilou VI, Fraser D, Kanasi E
… +9 more, Brenchley L, Greenwell-Wild T, Adade EE, Valm AM, Douagi I, Belkaid Y, Tran DT, Williams DW, Moutsopoulos NM
Nat Immunol
· 2026 Mar · PMID 41663813
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Immune responsiveness at barrier surfaces is tailored to the exposures of each tissue. In the oral mucosa, mechanisms by which a permeable epithelium coexists with diverse microbiota and maintains integrity during inflam...Immune responsiveness at barrier surfaces is tailored to the exposures of each tissue. In the oral mucosa, mechanisms by which a permeable epithelium coexists with diverse microbiota and maintains integrity during inflammatory pathology remain poorly understood. We compile a multiomics spatial map of this exposed mucosal microenvironment and uncover remarkable immune zonation with organization that is preserved even during inflammatory disease. At the tooth interface, we identify a dynamic epithelium underlined by a layer of neutrophils and a zone of antigen-presenting cell-lymphocyte aggregates. During disease, inflammatory zones expand and organize into immature tertiary lymphoid structures, suggesting local antibody production. Location-specific transcriptomes support a role for the stromal compartment in the spatial organization of immunity. This preserved immune zonation meets the demands for continuous protection of this vulnerable interface and suggests unique tissue-specific wiring of immunity at the human oral mucosal barrier.
Hayashi F, Mittl K, Dandekar R
… +34 more, Gerdts J, Hassan E, Schubert RD, Oshiro L, Loudermilk R, Greenfield A, Augusto DG, Havton G, Anumarlu S, Surapaneni A, Ramesh A, Tran E, Koshal K, Kizer K, Dreux J, Cagalingan AK, Schustek F, Flood L, Moore T, Kirkemo LL, Fisher IJ, Cooper T, Harms M, Gomez R, University of California, San Francisco MS-EPIC Team, Clelland CD, Sibener L, Cree BAC, Hauser SL, Hollenbach JA, Gee M, Wilson MR, Zamvil SS, Sabatino JJ
Nat Immunol
· 2026 Mar · PMID 41644766
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CD8 T cells are the dominant clonally expanded lymphocyte population in multiple sclerosis (MS) lesions but their clonal identity, function and antigen specificity are not well understood. A comprehensive single-cell RNA...CD8 T cells are the dominant clonally expanded lymphocyte population in multiple sclerosis (MS) lesions but their clonal identity, function and antigen specificity are not well understood. A comprehensive single-cell RNA-sequencing and T cell receptor-sequencing analysis of the cerebrospinal fluid and blood from individuals in the MS and control cohorts revealed a subset of 23 highly expanded and activated CD8 T cell clonotypes that were enriched predominantly in the cerebrospinal fluid in the MS cohort. Using unbiased and targeted antigen discovery approaches, six CD8 T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. Although the majority of mimotopes did not elicit functional responses, three of the expanded CD8 T cell receptors from patients with MS were reactive to EBV. EBV DNA and transcripts were detected in cerebrospinal fluid, including in patients with MS who had highly expanded EBV-specific CD8 T cells. These findings shed vital insight into the role of CD8 T cells in MS and support an important role of EBV in MS immunopathology.
Nat Immunol
· 2026 Mar · PMID 41634488
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Innate lymphoid cells (ILCs) are a diverse group of immune cells that possess many effector functions of T cells but lack somatically generated receptors. They have crucial roles in early immune responses and in maintain...Innate lymphoid cells (ILCs) are a diverse group of immune cells that possess many effector functions of T cells but lack somatically generated receptors. They have crucial roles in early immune responses and in maintaining tissue integrity. We review ILC developmental pathways and progenitors in mice, with a particular focus on adult bone marrow but also addressing fetal liver. We present recent insights into the earliest steps of ILC specification, as well as new evidence for developmental pathways that generate two functionally distinct types of natural killer cells. The anatomical locations where ILC progenitors are identified are outlined and evidence supporting ILC development in tissues examined. In addition, key transcriptional regulators that support ILC development are discussed. Although ILC and T-lineage cells use many of the same transcriptional controllers during development, we present new evidence indicating ILC transcriptional programs diverge from T-lineage programs at the earliest known steps of ILC lineage specification.
Gieselmann L, DeLaitsch AT, Rohde M
… +34 more, Radford C, Worczinski J, Ashurov A, Ahmadov E, Burger JA, Havenar-Daughton C, Deshpande S, Giovannoni F, Corti D, Kreer C, Ercanoglu MS, Schommers P, Georgiev IS, West AP, Knüfer J, Stumpf R, Kroidl A, Geldmacher C, Maganga L, William W, Ntinginya NE, Hoelscher M, Yang Z, Wei Q, Renfrow MB, Green TJ, Novak J, van Gils MJ, Gristick HB, Gruell H, Bloom JD, Seaman MS, Bjorkman PJ, Klein F
Nat Immunol
· 2026 Mar · PMID 41634487
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Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against mul...Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels. 007 targets an N332 glycan-independent V3 epitope, a site of the HIV-1 envelope protein (Env) vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryogenic electron microscopy structure revealed contacts with the V3 GD/NIR motif and interactions with N156 and N301 glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332 glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs. Bivalent 007 IgG was more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007's potential for HIV-1 prevention, therapy, functional cure and vaccine design.