N Nature Immunology · Dec 03, 2025 Single-cell multi-omic landscape reveals anatomical-specific immune features in adult and pediatric sepsis The anatomical source of infection is a major determinant of sepsis outcomes; however, how distinct sites shape immunity remains unclear. Here we applied multi-omic profiling, integrating single-cell transcriptomics, single-cell T cell receptor and B cell receptor sequencing, CITE-seq, bulk RNA sequencing and plasma proteomics, to analyze peripheral blood mononuclear cells and plasma from 281 adult and pediatric individuals with sepsis and controls. We identified an NR4A2+central memory CD4+T cell subset enriched in abdominal, pulmonary and skin sepsis, with features of exhaustion; genetic perturbations showedNr4a2loss improved survival, while overexpression worsened it. Proinflammatory CD8+T, natural killer and natural killer T subsets expressingCCL4,CCL3and tumor necrosis factor expanded in adult abdominal and pulmonary sepsis, while pediatric pulmonary sepsis featured proliferative CD14+monocytes, findings validated in external single-cell cohorts and confirmed in 164 independent individuals. Plasma proteomics revealed shared mediators including interleukin-6 and EN-RAGE across anatomical sites and ages. Together, our findings delineate anatomical-specific and age-specific immune programs in sepsis, highlighting candidate targets for precision immunotherapy. Immunological disorders Immunology biology
N Nature Immunology · Nov 28, 2025 A microenvironment-driven HLA-II-associated insulin neoantigen elicits persistent memory T cell activation in diabetes The antigenic landscape of autoimmune diabetes reflects a failure to preserve self-tolerance, yet how novel neoantigens emerge in humans remains incompletely understood. Here we designed an immunopeptidomics-based approach to probe HLA-II-bound, islet-derived neoepitopes in patients with type 1 diabetes. We uncovered a Cys→Ser transformation, conserved between mice and humans, that reshapes autoreactivity to insulin at the single-residue level. This transformation, which we call C19S, arises from oxidative remodeling of insulin in stressed pancreatic islets and also occurs in cytokine-activated antigen-presenting cells, contributing to a feed-forward loop of neoepitope formation and presentation. Despite involving just one amino acid, C19S is recognized by HLA-DQ8-restricted, register-specific CD4+T cells that expand at diabetes onset. These neoepitope-specific CD4+T cells lack regulatory potential but acquire a poised central memory phenotype that persists throughout disease progression. These findings reveal a distinct, microenvironment-driven route of neoantigen formation that fuels sustained autoreactivity in diabetes. Autoimmunity Immune tolerance MHC class II biology
N Nature Immunology · Nov 24, 2025 Enteric nervous system-derived VIP restrains differentiation of LGR5+stem cells toward the secretory lineage impeding type 2 immune programs Barrier homeostasis relies on a finely tuned interplay between the immune system, epithelial cells and commensal microbiota. Beyond these regulators, the enteric nervous system has recently emerged as a central hub coordinating intestinal immune responses, although its role in epithelial differentiation has remained largely unexplored. Here, we identify a neuroepithelial circuit in which vasoactive intestinal peptide (VIP)-positive enteric neurons act on VIPR1+epithelial stem cells to restrain both their proliferation and secretory lineage differentiation. Disruption of this pathway leads to an expansion of tuft cells, enhanced interleukin (IL)-25 production, activation of group 2 innate lymphoid cells (ILC2s) and induction of a type 2 immune response resembling worm expulsion. This phenotype occurs independently of the microbiota but is modulated by the IL-25R–ILC2–IL-13 axis and dietary solid food intake. Our findings expose the enteric nervous system as a critical regulator of epithelial fate decisions and immune balance, complementing established mechanisms that safeguard barrier integrity and mucosal homeostasis. Innate lymphoid cells Mucosal immunology Neuroimmunology biology
N Nature Immunology · Nov 24, 2025 Neuroepithelial VIP–VIPR1 interactions differentially control enteric type 1 and type 2 immunity The nervous and immune systems cooperate to regulate mucosal barrier integrity. Nevertheless, whether enteric neurons establish neuroepithelial interactions to coordinate immunity remains elusive. Here, we identified neuroepithelial interactions that differentially control intestinal type 1 and type 2 immunity. Gut epithelial cells expressed vasoactive intestinal peptide (VIP) receptor 1 (VIPR1), and chemogenetic modulation of enteric VIPergic neurons led to altered epithelial-derived cytokines. Epithelial-intrinsic deletion of Vipr1 resulted in diminished type 1 immunity, including reduced type 1 alarmins and intraepithelial lymphocytes. In contrast, epithelial Vipr1 deficiency led to enhanced type 2 immunity, comprising increased type 2 alarmins, tuft cells and activated group 2 innate lymphoid cells. Disruption of neuroepithelial VIP–VIPR1 interactions resulted in increased susceptibility to invasive bacterial infection, which contrasted with enhanced resistance to parasite infection. Our work identifies a multi-tissue axis that controls type 1 and type 2 immunity, deciphering how neuroepithelial interactions distinctively set gut immunity programs. Veiga-Fernandes and colleagues show that neuroepithelial interactions differentially control type 1 and type 2 enteric immunity via VIP–VIPR1 signaling. Mucosal immunology Neuroimmunology biology
N Nature Immunology · Nov 21, 2025 Pseudokinase STK40 limits T cell exhaustion through COP1-dependent degradation of AP1-family transcription factors Serine/threonine kinase 40 (STK40) belongs to the Tribbles family of pseudokinases, which serve as substrate adaptors for the CRL4COP1/DET1E3 ubiquitin ligase complex. Tribbles-1 and Tribbles-2 promote the degradation of CCAAT/enhancer-binding protein (C/EBP) transcription factors in hematopoietic cells. STK40 also regulates C/EBP proteins, and although some immune system functions have recently emerged, its specific role in cytotoxic T cell responses has not been characterized. Here we show that murine STK40 restricts homeostatic and antigen-driven T cell expansion. During chronic viral infection, T cell-specific deletion ofStk40improved viral clearance and reduced the proportion of terminally exhausted antigen-specific T cells. STK40-deficient T cells exhibited increased expression of markers of cell proliferation and AP-1 target genes. Biochemically, STK40 interacted with the AP-1 transcription factor c-Jun, and was required for its CRL4COP1/DET1-dependent proteasomal degradation. Collectively, our results identify the COP1/STK40 axis as a post-translational cell-intrinsic mechanism regulating T cell immunity. Post-translational modifications T cells biology mouse experiments
N Nature Immunology · Nov 21, 2025 Interferon-mediated NK cell activation increases cytolytic activity against T follicular helper cells and limits antibody response to SARS-CoV-2 Natural killer (NK) cells are innate lymphocytes known for their ability to kill infected or malignant cells, but they have an overlooked role in regulating antibody responses. In mice, NK cells can kill T follicular helper (TFH) cells, decreasing somatic hypermutation and antibody titers. Although human NK cell activation correlates with poor vaccine response, the mechanisms of NK cell regulation of adaptive immunity in humans are poorly understood. Here we found that, in ancestral severe acute respiratory syndrome coronavirus 2 infection, individuals with the broadest neutralization profile had fewer NK cells that expressed inhibitory and immaturity markers, whereas NK cells from narrow neutralizers were highly activated and expressed interferon-stimulated genes. ISG-mediated activation in NK cells from healthy donors increased cytotoxicity toward induced TFH-like cells via NKG2D and NKp30. This work reveals that NK cell activation and dysregulated inflammation play a role in poor antibody response to severe acute respiratory syndrome coronavirus 2 and opens exciting avenues for designing improved vaccines and adjuvants to target emerging pathogens. Antibodies Infectious diseases Innate lymphoid cells biology mouse experiments
N Nature Immunology · Nov 21, 2025 Sequential lymphotoxin-β receptor and retinoic acid receptor signals regulate cDC2 fate Type 2 conventional dendritic cells (cDC2s) are functionally and phenotypically heterogenous. Previous work in mice and humans identified two cDC2 subsets (cDC2As and cDC2Bs) and a monocytic DC3 subset. However, the microenvironmental cues governing their distinct differentiation pathways remain unclear. Here, we delineate mouse cDC2 lineage relationships and the sequential signals required for cDC2A maintenance. We show that cDC2s, arising from the CLEC9A+cDC progenitor, encompass T-BET-expressing cDC2As and two cDC2B subsets distinguished by MGL2 expression, with monocytic DC3s exhibiting transcriptional overlap withMgl2−cDC2Bs. Among these subsets, T-BET+cDC2As dominate the spleen where they require cell-intrinsic retinoic acid signaling to sustain their differentiation via Notch signals. Lymphotoxin-β receptor signaling on splenic cDC2s limits F-actin content retaining cDC2s at sites of retinol delivery. In summary, these data establish the developmental and transcriptional relationships between diverse cDC2 subsets and identify signals that regulate their prevalence in specific lymphoid tissues. Immunology Innate immune cells biology mouse experiments
N Nature Immunology · Nov 18, 2025 Analysis of the three-dimensional genome of exhausted CD8+T cells reveals a critical role of IRF8 in their differentiation and functions in cancer CD8+T cells are rendered exhausted in cancer, accompanied by extensive changes in the epigenome. However, whether and how higher-order chromatin organization is involved in exhausted CD8+T cell differentiation is unclear. Here, we show extensive changes in the three-dimensional genome during T cell exhaustion associated with changes in gene transcription. Moreover, we identified interferon regulatory factor 8 (IRF8) as an essential transcription factor involved in reorganization of the spatial proximity between enhancers and promoters of genes associated with exhausted T cell differentiation. IRF8 deficiency inhibited the differentiation of exhausted CD8+T cells and their antitumor function. Mechanistically, IRF8 bound to genes associated with exhausted T cell differentiation and promoted the formation of intra-TAD chromosomal loops. At the loop anchor regions, IRF8 recruited CTCF to form active chromosomal structures to regulate gene transcription. These results thus identify a critical role of IRF8-dependent chromatin topology during exhausted CD8+T cell differentiation. Adaptive immunity Immunology
N Nature Immunology · Nov 17, 2025 Fibroblastic FLT3L supports lymph node dendritic cells in the interfollicular niche Dendritic cell (DC) homeostasis is maintained in secondary lymphoid organs (SLOs) by Fms-like tyrosine kinase 3 ligand (FLT3L). The specific niche providing this DC growth factor within human and mouse SLOs is unclear. Here we show that Gremlin1 (GREM1)-expressing lymph node fibroblastic reticular cells (FRCs) support DC homeostasis via provision of FLT3L. Grem1-expressing FRCs colocalize with DCs and expressFLT3LG/Flt3lin human and mouse lymph nodes. Using a new genetic model, we provide evidence that FLT3L produced by GREM1+FRCs maintains lymph node DC precursors (preDCs) and both conventional (cDCs) and plasmacytoid DCs (pDCs). Spatial transcriptomics and cytofluorometry reveal that GREM1+FRC-derived FLT3L supports not only proliferation, but also survival of lymph node preDCs and cDCs within the interfollicular zone (IFZ). Functionally, loss of GREM1+FRC-derived FLT3L impairs cDC activation of antigen-specific T cell responses to both immunization and infection. These findings provide key mechanistic insights underlying stromal cell support of DC homeostasis and function. Dendritic cells Lymph node
N Nature Immunology · Nov 17, 2025 Thrombospondin-1–CD47 signaling contributes to the development of T cell exhaustion in cancer T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8+T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin–NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1–CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1–CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy. Tumour immunology
N Nature Immunology · Nov 12, 2025 TSLP links intestinal nutrient sensing with amplification of the ILC2–tuft cell circuit Group 2 innate lymphocytes (ILC2s) are prevalent in small intestine but their role during homeostasis is unclear. Here we show that thymic stromal lymphopoietin (TSLP)—a cytokine implicated in ILC2 activation—is expressed constitutively in subepithelial fibroblasts, including telocytes and crypt-associated trophocytes, which are specialized fibroblasts necessary to sustain epithelial identity. Feeding increases TSLP and induces ILC2 type 2 cytokines that are attenuated by deletion of TSLP in fibroblasts or TSLP receptor on ILC2s. Both mouse and human intestinal fibroblasts express receptors for glucagon-like peptide-2 (GLP-2)—an intestinotrophic growth factor released by enteroendocrine cells following food intake. GLP-2 promotes intestinal TSLP in mouse and human intestinal fibroblasts, and TSLP-dependent ILC2 activation and tuft cell hyperplasia in mice, thus linking nutrient detection with ILC2-mediated amplification of the tuft cell chemosensory circuit that promotes epithelial surveillance of ingested cargo. Innate lymphoid cells Mucosal immunology
N Nature Immunology · Nov 11, 2025 Single-cell analysis reveals cell death as driver of NLRP3-mediated secretion of IL-1β in human monocytes Interleukin-1β (IL-1β) is a key proinflammatory cytokine with critical roles in infections and inflammatory diseases, yet the mechanisms regulating its release from human monocytes remain unclear. Here we used a suite of single-cell approaches, including integrated live-cell imaging of secretion and cell fate, flow cytometry and high-content imaging, to investigate IL-1β secretion dynamics in lipopolysaccharide-stimulated primary human peripheral blood CD14+monocytes. We found marked heterogeneity: a large fraction of cells remained viable and contributed negligibly to IL-1β secretion, challenging established models. Instead, a small subset (5–10%) undergoing canonical NLRP3 inflammasome activation and GSDMD-dependent pyroptosis produced the majority of secreted IL-1β, with a smaller contribution from apoptotic cells transitioning to secondary necrosis. Single-cell profiling of CD14+monocytes from patients with cryopyrin-associated periodic syndrome confirmed lytic cell death as the driver of pathological IL-1β release. These findings redefine IL-1β as a damage-associated molecular pattern, secreted predominantly by dying monocytes. Cell death and immune response Inflammasome
N Nature Immunology · Nov 04, 2025 Peanut allergy oral immunotherapy drives single-cell multi-omic changes in peanut-reactive T cells associated with sustained unresponsiveness Oral immunotherapy (OIT) is the only U.S. Food and Drud Administration-approved treatment for peanut allergy. Peanut-reactive (pr) CD4+T cells are pivotal in peanut allergy pathogenesis and OIT-induced desensitization. However, the underlying pr CD4+T cell immune mechanisms leading to sustained unresponsiveness after OIT discontinuation are largely unknown. We analyzed single-cell RNA and protein immunophenotypes and T cell receptor repertoires of pr CD4+T cells from a phase 2 peanut OIT trial cohort. We identified increased cytotoxicity-related phenotypes and type 1 helper cytotoxic T lymphocyte-like cell clonal expansion during OIT, while type 2 helper T (TH2) cell-related phenotypes and TH2-like cell clonal expansion decreased. OIT participants achieving sustained unresponsiveness were distinguished by lower baseline TH2-related phenotypes, elevated post-OIT cytotoxicity-related pr effector T cell gene signatures and higher CD39 expression in pr regulatory T cells. These findings clarify OIT-induced CD4+T cell tolerance mechanisms and can guide effective allergen-specific OIT strategies. Immunological disorders Immunosuppression
N Nature Immunology · Oct 29, 2025 Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion Contrary to tumor-infiltrating T cells with dysfunctional mitochondria, tumor-associated macrophages (TAMs) preserve their mitochondrial activity in the nutrient-limited tumor microenvironment (TME) to sustain immunosuppression. Here we identify TNF receptor-associated protein-1 (TRAP1), a mitochondrial HSP90 chaperone, as a metabolic checkpoint that restrains oxidative respiration and limits macrophage suppressive function. In the TME, TRAP1 is downregulated through TIM4–AMPK signaling, and its loss enhances immunoinhibitory activity, limits proinflammatory capacity and promotes tumor immune escape. Mechanistically, TRAP1 suppression augments electron transport chain activity and elevates the α-ketoglutarate/succinate ratio, remodeling mitochondrial homeostasis. The resulting accumulation of α-ketoglutarate further potentiates JMJD3-mediated histone demethylation, establishing transcriptional programs that reinforce an immunosuppressive state. Restoring TRAP1 by targeting TIM4 and JMJD3 reprograms TAMs, disrupts the immune-evasive TME and bolsters antitumor immunity. These findings establish TRAP1 as a critical regulator integrating metabolic and epigenetic control of suppressive TAM function and position the TRAP1 pathway as a promising target for cancer immunotherapy. Chaperones Immunosuppression
N Nature Immunology · Oct 28, 2025 Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3–6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors. Chronic inflammation Neutrophils
N Nature Immunology · Oct 27, 2025 Transcriptional regulator SATB1 limits CD8+T cell population expansion and effector differentiation in chronic infection and cancer CD8+T cells are major mediators of antiviral and antitumor immunity. During persistent antigen stimulation as in chronic infection and cancer, however, they differentiate into exhausted T cells that display impaired functionality. Precursors of exhausted T (TPEX) cells exhibit stem-like properties, including high proliferative, self-renewal and developmental potential, and are responsible for long-term CD8+T cell responses against persistent antigens. Here we identify the chromatin organizer and transcriptional regulator SATB1 as a major regulator of exhausted CD8+T cell differentiation. SATB1 was specifically expressed in TPEXcells where it limited population expansion and effector differentiation while preserving functionality of CD8+T cells. SATB1 downregulation was required for TPEXcell-to-effector cell differentiation in chronic infection and contributed to coordinated effector and memory differentiation in acute viral infection. DNA binding of SATB1 regulated gene expression both dependent and independent of chromatin accessibility. Finally, SATB1 limited antitumor CD8+and chimeric antigen receptor T cell immunity. Overall, our results identify SATB1 as a central regulator of precursor fate and effector differentiation of CD8+T cells both in infection and in cancer. Immunotherapy Infection
N Nature Immunology · Oct 22, 2025 A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice Large-scale, unbiased single-cell genomics studies of complex developmental compartments, such as hematopoiesis, have inferred novel cell states and trajectories; however, further characterization has been hampered by difficulty isolating cells corresponding to discrete genomic states. To address this, we present a framework that integrates multimodal single-cell analyses (RNA, surface protein and chromatin) with high-dimensional flow cytometry and enables semiautomated enrichment and functional characterization of diverse cell states. Our approach combines transcription factor expression with chromatin activity to uncover hierarchical gene regulatory networks driving these states. We delineated and isolated rare bone marrow Lin−Sca−CD117+CD27+multilineage cell states (‘MultiLin’), validated predicted lineage trajectories and mapped differentiation potentials. Additionally, we used transcription factor activity on chromatin to trace and isolate multilineage progenitors undergoing multipotent to oligopotent lineage restriction. In the proposed model of steady-state hematopoiesis, discrete states governed developmental trajectories. This framework provides a scalable solution for isolating and characterizing novel cell states across different biological systems. Cell biology Gene regulation in immune cells Haematopoietic stem cells Myelopoiesis RNA sequencing
N Nature Immunology · Oct 22, 2025 Transcriptional and epigenetic targets of MEF2C in human microglia contribute to cellular functions related to autism risk and age-related disease MEF2Cencodes a transcription factor that is critical in nervous system development. Here, to examine disease-associated functions of MEF2C in human microglia, we profiled microglia differentiated from isogenicMEF2C-haploinsufficient andMEF2C-knockout induced pluripotent stem cell lines. Complementary transcriptomic and functional analyses revealed that loss of MEF2C led to a hyperinflammatory phenotype with broad phagocytic impairment, lipid accumulation, lysosomal dysfunction and elevated basal inflammatory cytokine secretion. Genome-wide profiling of MEF2C-bound sites coupled with the active regulatory landscape enabled inference of its transcriptional functions and potential mechanisms for MEF2C-associated cellular functions. Transcriptomic and epigenetic approaches identified substantial overlap with idiopathic autism datasets, suggesting a broader role of human microglial MEF2C dysregulation in idiopathic autism. In a mouse xenotransplantation model, loss of MEF2C led to morphological, lysosomal and lipid abnormalities in human microglia in vivo. Together, these studies reveal mechanisms by which reduced microglial MEF2C could contribute to the development of neurological diseases. Chromatin Gene regulation in immune cells Haematopoietic stem cells Neuroimmunology
N Nature Immunology · Oct 21, 2025 Single-cell RNA profiling of blood CD4+T cells identifies distinct helper and dysfunctional regulatory clusters in children with SLE To characterize the complexity of the CD4⁺ T cell compartment in patients with systemic lupus erythematosus (SLE), we performed single-cell RNA sequencing of sorted blood CD4⁺ T cells from pediatric patients and healthy donors. We identified naive, memory, regulatory T (Treg) cell, proliferative and interferon-stimulated gene-high (ISG-high) clusters. Within the memory compartment, both follicular and peripheral helper cells were expanded in patients with lupus nephritis and/or high disease activity. Cytotoxic signatures were enriched in effector memory T cells re-expressing CD45RA (TEMRA), as well as in two memory subclusters, one of which overlapped with T helper 10-like cells (TH10). Notably, we observed an expansion of dysfunctional Tregcells in patients with lupus nephritis, along with upregulation ofTLR5andFCRL3in SLE-naive Tregcells, suggesting a potential link with mucosal microbial dysbiosis. These findings highlight distinct CD4⁺ T cell subsets that may contribute to aberrant antibody responses and impaired immune regulation in SLE. Autoimmunity Chronic inflammation
N Nature Immunology · Oct 15, 2025 The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells The co-inhibitory receptor TIGIT suppresses excessive immune responses in autoimmune conditions while also restraining antitumor immunity. In viral infections, TIGIT alone does not affect viral control but has been shown to limit tissue pathology. However, the underlying mechanisms are incompletely understood. Here we found TIGIT+ T cells to express not only an immunoregulatory gene signature but also a tissue repair gene signature. Specifically, after viral infection, TIGIT directly drives expression of the tissue growth factor amphiregulin (Areg), which is strongly reduced in the absence of TIGIT. We identified regulatory T (Treg) cells, but not CD8+ T cells, as the critical T cell subset mediating these tissue-protective effects. In Treg cells, TIGIT engagement after T cell antigen receptor stimulation induces the transcription factor Blimp-1, which then promotes Areg production and tissue repair. Thus, we uncovered a nonclassical function of the co-inhibitory receptor TIGIT, wherein it not only limits immune pathology by suppressing the immune response but also actively fosters tissue regeneration by inducing the tissue growth factor Areg in T cells. Joller and colleagues show that the co-inhibitory receptor TIGIT induces the expression of the tissue growth factor amphiregulin (Areg) in regulatory T cells and contributes to tissue repair in response to viral infection. Adaptive immunity Cellular immunity Infectious diseases Inflammatory diseases
N Nature Immunology · Oct 15, 2025 Influenza vaccine based on AS03-adjuvanted chimeric HA induces long-lived stalk-specific plasma cells in bone marrow and lymph nodes of nonhuman primates Current influenza vaccines face challenges due to antigenic evolution of the circulating virus and waning immunity in humans. Here we investigated the durability of humoral immunity induced by an influenza vaccine based on AS03-adjuvanted chimeric hemagglutinin (cHA) in nonhuman primates (NHPs). Two groups of NHPs received two doses of a seasonal quadrivalent influenza vaccine, followed by sequential immunization with split virus cHA vaccines cH8/1N1, and cH5/1N1. One group received cHA immunizations with AS03 adjuvant. We monitored serum antibodies and long-lived plasma cells in bone marrow for nearly 2 years after the final vaccination. cHA vaccines induced stalk-specific antibody responses. The addition of AS03 enhanced both the magnitude and durability of humoral immunity by establishing long-lived plasma cells in the bone marrow and lymph nodes for nearly 2 years. Passive transfer of NHP serum provided protection against challenge with heterologous influenza A virus strains in mice. This study highlights the potential of the AS03-adjuvanted chimeric HA vaccine strategy to provide durable and broadly protective humoral immunity. Adjuvants Protein vaccines
N Nature Immunology · Oct 14, 2025 Tonic type I interferon signaling optimizes the antiviral function of plasmacytoid dendritic cells Plasmacytoid dendritic cells (pDCs) mount powerful antiviral type I interferon (IFN-I) responses, yet only a fraction of pDCs produces high levels of IFN-I. Here we report that peripheral pDCs in naive mice comprise three subsets (termed A, B and C) that represent progressive differentiation stages. This heterogeneity was generated by tonic IFN-I signaling elicited in part by the cGAS/STING and TLR9 DNA-sensing pathways. A small ‘IFN-I-naive’ subset (pDC-A) could give rise to other subsets; it was expanded in STING deficiency or after the IFN-I receptor blockade, but was abolished by exogenous IFN-I. In response to RNA viruses, pDC-A showed increased Bcl2-dependent survival and superior IFN-I responses, but was susceptible to virus infection. Conversely, the majority of pDCs comprised the ‘IFN-I-primed’ subsets (pDC-B/C) that showed lower IFN-I responses and poor survival, but did not support virus replication. Thus, tonic IFN-I signaling decreases the cytokine-producing capacity and survival of pDCs but increases their virus resistance, facilitating optimal antiviral responses. Interferons Plasmacytoid dendritic cells
N Nature Immunology · Oct 14, 2025 Transient tissue residency and lymphatic egress define human CD56brightNK cell homeostasis Human tissue-resident (TR) CD56brightnatural killer (NK) cells can be identified by expression of integrins and chemokine receptors inferred from murine studies, but many aspects of their homeostasis are unclear. Here we used an integrated approach of dynamic human, humanized mouse and non-human primate models and sampling of efferent lymph fluid to determine recirculation and TR patterns of human NK cells. By intravascular labeling, we showed that CD56brightNK cells access tissue niches at steady state. Furthermore, in human liver transplantation, donor-derived CD56brightNK cells represent the dominant TR NK cell population early after transplantation, but are replaced over time by infiltrating recipient NK cells that establish TR traits, a process partly regulated by Runx3. Transient TR CD56brightNK cells recirculated via lymphatics, displaying a consistent phenotype detectable in draining lymph nodes and efferent lymph fluid, and waned from peripheral blood on lymph node egress blockade. Finally, CD56dimNK cells, constrained to vasculature at steady state, entered lymph nodes upon inflammation. This study provides a mechanistic framework for the transient tissue residency and recirculation pattern of human NK cell populations. Lymphoid tissues NK cells
N Nature Immunology · Oct 08, 2025 Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells Regulatory T (Treg) cells, expressing the transcription factor Foxp3, are obligatory gatekeepers of immune responsiveness, yet the mechanisms by which Foxp3 governs the Tregtranscriptional network remain incompletely understood. Using a novel chemogenetic system of inducible Foxp3 protein degradation in vivo, we found that while Foxp3 was indispensable for the establishment of transcriptional and functional programs of newly generated Tregcells, Foxp3 loss in mature Tregcells resulted in minimal functional and transcriptional changes under steady state. This resilience of the Foxp3-dependent program in mature Tregcells was acquired over an unexpectedly long timescale; however, in settings of severe inflammation, Foxp3 loss led to a pronounced perturbation of Tregcell transcriptome and fitness. Furthermore, tumoral Tregcells were uniquely sensitive to Foxp3 degradation, which led to impairment in their suppressive function and tumor shrinkage in the absence of pronounced adverse effects. These studies demonstrate a context-dependent differential requirement for Foxp3 for Tregtranscriptional and functional programs. Gene regulation in immune cells Immune tolerance
N Nature Immunology · Oct 07, 2025 Age-dependent Zap70 expression in thymocytes regulates selection of the neonatal regulatory T cell repertoire The Foxp3⁺ regulatory T (Treg) cell repertoire carries age-dependent biases, with neonatal subsets enriched for highly self-reactive clones. However, the thymocyte features distinguishing neonatal from adult Tregselection remain unclear. Here, we show that neonatal double-positive mouse thymocytes, unlike their adult counterparts, fail to upregulate Zap70 during thymic selection, creating a calcium signaling bottleneck. This attenuated Zap70-dependent signaling limits negative selection, allowing highly self-reactive clones to evade deletion. Modulating Zap70 expression alters this balance; reducing Zap70 in adults rescues development of these clones, whereas increasing Zap70 in neonates enforces their deletion. Similarly, enhancing neonatal calcium signaling via increased LAT Y136-mediated PLCγ1 activation promotes clonal deletion. Analysis of pediatric human thymi reveals that ZAP70 expression remains low during the first year of life, aligning with the peak window for thymic Tregcell development. These findings suggest that age-dependent Zap70 expression regulates negative selection and thymic Tregcell development. CD4-positive T cells Central tolerance
N Nature Immunology · Oct 06, 2025 Profiling of HIV-1 elite neutralizer cohort reveals a CD4bs bnAb for HIV-1 prevention and therapy Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by envelope diversity and rapid viral escape. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies with highest antiviral activity. From 831 expressed monoclonal antibodies, we identified 04_A06, a VH1-2-encoded broadly neutralizing antibody to the CD4 binding site with remarkable breadth and potency against multiclade pseudovirus panels (geometric mean half-maximal inhibitory concentration = 0.059 µg ml−1, breadth = 98.5%, 332 strains). Moreover, 04_A06 was not susceptible to classic CD4 binding site escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed an unusually long 11-amino-acid heavy chain insertion that facilitates interprotomer contacts with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody-Mediated Prevention trials (geometric mean half-maximal inhibitory concentration = 0.082 µg ml−1, breadth = 98.4%, 191 virus strains), and in silico modeling for 04_A06LS predicted prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention of HIV-1 infection. HIV infections Humoral immunity
N Nature Immunology · Sep 30, 2025 Spatiotemporal interaction of immune and renal cells controls glomerular crescent formation in autoimmune kidney disease Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney diseases and is characterized by glomerular crescent formation with proliferation of parietal epithelial cells (PECs). However, the underlying mechanisms of glomerular crescent formation are incompletely understood. Here we provide a high-resolution spatial kidney cell atlas of 57 samples from patients with RPGN (ANCA-associated GN, lupus nephritis and anti-glomerular basement membrane-GN) to characterize the cell signaling pathways in glomerular crescent development. Early platelet-derived growth factor (PDGF) signaling from epithelial and mesangial cells caused PEC activation and proliferation in glomerular crescents, whereas later transforming growth factor (TGF)-β signaling from macrophages, T cells and epithelial and mesangial cells triggered expression of extracellular matrix components in PECs associated with glomerulosclerosis and disease progression. These findings were similar across the different GNs and were functionally validated in experimental GN by PDGF and TGFβ blockade. These results highlight a spatiotemporally conserved progression program into glomerular crescents and sclerosis and indicate new treatment options for autoimmune kidney disease. Autoimmune diseases Immunopathogenesis Lupus nephritis
N Nature Immunology · Sep 29, 2025 Chemotherapy-induced CA-repeat DNA fragments in breast cancer trigger antitumor immune responses Damage-associated molecular patterns generated by cancer treatment can modulate antitumor immunity, but the underlying mechanisms of this effect are unclear. Here we show that CA-enriched DNA fragments resulting from DNA-damaging chemotherapy in MSH2-low tumors preferentially bind cGAS with strong affinity and form biomolecular condensates by phase separation in the cytoplasm, resulting in antitumor immunity. However, classical CA-poor DNAs released from MSH2-high tumor cells engage AIM2, resulting in immunosuppression by upregulating PD-L1 and IDO. Intratumoral administration of CA-rich DNA fragments enhanced antitumor immunity in syngrafted PyMT tumors. Clinically, CA-rich DNA abundance in breast cancer following chemotherapy was associated with increased tumor-antigen-reactive T cells and better chemotherapeutic responses. Therefore, different tumor DNA fragments can trigger opposing immune responses depending on their preference for differential sensors. This study highlights another mechanistic link between genome instability and immune modulation and the therapeutic potential of CA-rich DNAs to enhance antitumor immunity. Adjuvants Cancer therapy Tumour immunology
N Nature Immunology · Sep 29, 2025 Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections Plasmacytoid dendritic cells (pDCs) are major producers of type I/III interferons. As interferons are crucial for antiviral defense, pDCs are assumed to play an essential role in this process; however, robust evidence supporting this dogma is scarce. Genetic or pharmacological manipulations that eliminate pDCs or disrupt their interferon production often affect other cells, confounding interpretation. Here, to overcome this issue, we engineered pDC-less mice that are specifically and constitutively devoid of pDCs by expressing diphtheria toxin under coordinated control of theSiglechandPacsin1genes, uniquely coexpressed in pDCs. pDC-less mice mounted protective immunity against systemic infection with mouse cytomegalovirus and showed higher survival and less lung immunopathology to intranasal infection with influenza virus and SARS-CoV-2. Thus, contrary to the prevailing dogma, we revealed that pDCs and their interferons are dispensable or deleterious during several viral infections. pDC-less mice will enable rigorously reassessing the roles of pDCs in health and disease. Cell biology Immunology
N Nature Immunology · Sep 24, 2025 A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues Fibroblasts sculpt the architecture and cellular microenvironments of various tissues. Here we constructed a spatially resolved atlas of human skin fibroblasts from healthy skin and 23 skin diseases, with comparison to 14 cross-tissue diseases. We define six major skin fibroblast subtypes in health and three that are disease-specific. We characterize two fibroblast subtypes further as they are conserved across tissues and are immune-related. The first, F3: fibroblastic reticular cell-like fibroblast (CCL19+CD74+HLA-DRA+), is a fibroblastic reticular cell-like subtype that is predicted to maintain the superficial perivascular immune niche. The second, F6: inflammatory myofibroblasts (IL11+MMP1+CXCL8+IL7R+), characterizes early human skin wounds, inflammatory diseases with scarring risk and cancer. F6: inflammatory myofibroblasts were predicted to recruit neutrophils, monocytes and B cells across multiple human tissues. Our study provides a harmonized nomenclature for skin fibroblasts in health and disease, contextualized with cross-tissue findings and clinical skin disease profiles. Cancer Immunological disorders Immunology
N Nature Immunology · Sep 22, 2025 Spatial and functional diversity of innate lymphoid cells in the human female genital tract may contribute to antiviral responses to HIV Innate lymphoid cells (ILCs) are tissue-resident lymphocytes specialized in cytokine secretion that lack antigen-specific receptors. The contribution of ILCs to antiviral mucosal immunity in humans, particularly in the female genital tract (FGT), remains unexplored. Here we resolved human FGT ILC diversity by spectral flow cytometry and CITE-seq, spatial location within genital anatomical regions using ChipCytometry, and determined homeostatic function and antiviral responses. We uncovered spatial and functional specializations of genital ILC subsets under homeostasis, with compartmentalized age-related and pregnancy-related changes. CD161 expression differentially discriminated ILC subsets preloaded with cytokines at steady state. We identified a unique NKp44+CCR6+ILC3 subset in the endometrium that actively degranulated at homeostasis and was located in lymphoid aggregates surrounded by B cells and T cells. By contrast, ILC1s were found scattered, enriched in the ectocervix and located close to the epithelium. Following in vitro HIV stimulation, genital ILCs displayed rapid subset-specific antiviral responses. These findings reveal distinct tissue and subset-specific features of FGT ILCs and their capacity to immediately respond to viral stimuli, providing a foundation for future studies to determine the potential role of ILCs in mucosal immune protection in the FGT. Imaging the immune system Infection Innate lymphoid cells Mucosal immunology Virology
N Nature Immunology · Sep 19, 2025 STING signals to NF-κB from late endolysosomal compartments using IRF3 as an adaptor NF-κB is central for activation of immune responses. Cytosolic DNA activates the cGAS–STING pathway to induce type I interferons (IFNs) and signaling through NF-κB, thus instigating host defenses and pathological inflammation. However, the mechanism underlying STING-induced NF-κB activation is unknown. Here we report that STING activates NF-κB in a delayed manner, following exit from the Golgi to endolysosomal compartments. Activation of NF-κB is dependent on the IFN-inducing transcription factor IRF3 but is independent of type I IFN signaling. This activation pattern is evolutionarily conserved in tetrapods. Mechanistically, the monomer IRF3 is recruited to STING pS358, with delayed kinetics relative to IRF3 recruitment to STING pS366, which promotes type I IFN responses. IRF3 engagement with STING pS358 induces trafficking to late endolysosomal compartments, supporting recruitment of TRAF6 and activation of NF-κB. We identify a TRAF6 binding motif in IRF3 that facilitates recruitment of TRAF6. This work defines a signaling surface on STING and a function for IRF3 as an adaptor in immune signaling. These findings indicate that STING signaling to NF-κB is enabled only within a short time window between exit from the Golgi and lysosomal degradation, possibly limiting inflammation under homeostatic and danger-sensing conditions. Innate immunity Signal transduction
N Nature Immunology · Sep 18, 2025 Epigenetic imprinting in innate lymphoid cell precursors directs the lineage segregation of innate lymphoid cells Innate lymphoid cells (ILCs) are essential for mucosal homeostasis, but the epigenetic regulation of their lineage segregation remains elusive. Here we simultaneously profiled the single-cell DNA methylome, chromatin accessibility and transcriptome of ILC subsets and ILC precursors (ILCPs) and found that ILCPs could be divided into two subgroups (ILCP1 and ILCP2). ILCP2s had highly heterogeneous DNA methylation profiles and could be divided into three groups according to their DNA methylation characteristics, which matched those of ILC subsets. We identified the signature methylation regions (SMRs) of each ILC subset and traced the DNA methylation imprinting during ILCP differentiation. ILCP2s with hypomethylated SMRs characteristic of ILC subsets differentiated into those subsets. DNA methylation editing of SMRs suppressed ILC lineage segregation, while deletion ofDnmt1in ILCPs abrogated the heterogeneous distribution of SMRs and resulted in ILC differentiation defects. These findings provide evidence that epigenetic imprinting determines lineage segregation during immune cell development. Lymphocytes Mucosal immunology
N Nature Immunology · Sep 15, 2025 Lymph nodes fuel KLF2-dependent effector CD8+T cell differentiation during chronic infection and checkpoint blockade Exhausted CD8+T (TEX) cell responses are maintained by precursors of exhausted T (TPEX) cells that possess high self-renewal and developmental potential. TPEXcells also drive the proliferative burst of effector T cells upon therapeutic immune checkpoint blockade (ICB). However, the spatial context and signals that regulate their differentiation and function are not well defined. Here we identify developmental and functional compartmentalization of TPEXand TEXcells across secondary lymphoid organs during chronic infection. We show that stem-like CD62L+TPEXand effector-like CX3CR1+TEXcells constitute a distinct developmental lineage that is promoted by the lymph node (LN) microenvironment and dependent on the transcription factor KLF2. LNs act as a niche in which migratory dendritic cells provide antigen and costimulatory signals to maintain the proliferative fitness of CD62L+TPEXcells and generation of CX3CR1+TEXcells. Moreover, LNs exclusively drive the proliferative burst and systemic dissemination of CX3CR1+TEXcells during ICB. Thus, our findings identify a unique role for LNs in the maintenance of T cell differentiation and function during systemic chronic infection and ICB therapy. CD8-positive T cells Immunotherapy Infection Tumour immunology
N Nature Immunology · Sep 15, 2025 Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response The formation of membrane pores by cleaved N-terminal gasdermin D (GSDMD-NT) results in the release of cytokines and inflammatory cell death, known as pyroptosis. Blocking GSDMD-NT pores is an attractive and promising strategy for mitigating inflammation. Here we demonstrate that SK56, an artificial intelligence-screened peptide, effectively obstructs GSDMD-NT pores and inhibits pyroptosis and cytokine release in macrophages and human peripheral blood leukocyte-induced pyroptosis. SK56 prevents septic death induced by lipopolysaccharide or cecal ligation and puncture surgery in mice. SK56 does not influence cleavage of interleukin-1β or GSDMD. Instead, SK56 inhibits the release of cytokines from pyroptotic macrophages, mitigates the activation of primary mouse dendritic cells triggered by incubation with pyroptotic cytomembranes and prevents widespread cell death of human alveolar organoids in an organoid–macrophage coculture model. SK56 blocks GSDMD-NT pores on lipid-bilayer nanoparticles and enters pyroptotic macrophages to inhibit mitochondrial damage. SK56 presents new therapeutic possibilities for counteracting inflammation, which is implicated in numerous diseases. Cell death and immune response Inflammatory diseases Necroptosis Sepsis
N Nature Immunology · Sep 15, 2025 A spatial map of MAPK-activated immunosuppressive myeloid populations in pediatric low-grade glioma Pediatric low-grade gliomas (pLGGs) are mitogen-activated protein kinase (MAPK) pathway-activated brain tumors prevalent in children and are associated with morbidity despite favorable survival. Here using imaging mass cytometry, we spatially characterized at the single-cell level the tumor microenvironment (TME) of 120 pLGG cases, considering age, molecular drivers, brain location and tumor subtype. Our analysis identified myeloid cells—including resident microglia and bone marrow-derived macrophages—as the predominant immune population in the TME, particularly in optic pathway tumors. Additionally, we discovered an immune signature predictive of progression-free survival. Spatial analysis identified specific cellular interactions, notably myeloid–myeloid contacts and macrophage-enriched regions harboring MAPK-activated, TIM-3+myeloid cells, suggesting an immunosuppressive TME. Our study provides a comprehensive resource on the immune landscape of these pLGGs and underscores the immunosuppressive role of diverse myeloid infiltrates. These findings also indicate that combining TIM-3 blockade with MAPK inhibition might be a promising therapeutic strategy to target both the TME and oncogenic MAPK activation in pLGG tumors. Cancer therapy Imaging the immune system Tumour immunology
N Nature Immunology · Sep 11, 2025 Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration Interleukin-18 (IL-18) is an acute-phase proinflammatory molecule crucial for mediating viral clearance by activating T helper 1 CD4+T cells, cytotoxic CD8+T cells and natural killer (NK) cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18-stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures the restoration of immune competence after acute insults such as stress, infection, chemotherapy and radiation. NK cells suppress thymus recovery by aberrantly targeting thymic epithelial cells, which act as the master regulators of organ function and regeneration. Together, our data reveal a new pathway regulating tissue regeneration in the thymus and suggest IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy due to its capacity to elicit a type 1 immune response, these findings also offer insight into potential off-target effects. Bone marrow transplantation Interleukins Lymphopoiesis Thymus
N Nature Immunology · Sep 09, 2025 Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity CD4+T follicular helper (TFH) cells support tailored B cell responses against multiple classes of pathogens. To reveal how diverse TFHphenotypes are established, we profiled mouse TFHcells in response to viral, helminth and bacterial infection. We identified a core TFHsignature that is distinct from CD4+T follicular regulatory and effector cells and identified pathogen-specific transcriptional modules that shape TFHfunction. Cytokine-transcriptional TFHprogramming demonstrated that type I interferon and TGFβ signaling direct individual TFHphenotypes to instruct B cell output. Cytokine-directed TFHtranscriptional phenotypes are shared within human germinal centers, but distinct TFHphenotypes dominate between donors and following immune challenge or in antibody-mediated disease. Finally, we identified new cell surface markers that align with distinct TFHphenotypes. Thus, we provide a comprehensive resource of TFHdiversity in humans and mice to enable immune monitoring during infection and disease and to inform the development of context-specific vaccines. Cytokines Gene regulation in immune cells Lymphocyte differentiation
N Nature Immunology · Sep 08, 2025 Distinct roles for B cell-derived LTα3 and LTα1β2 in TNF-mediated ileitis Crohn’s disease pathology is modeled in TNFΔARE+/−mice that overproduce tumor necrosis factor (TNF) to drive disease through TNF receptors. An alternative ligand for TNF receptors, soluble LTα3, is produced by B cells, but has received scarce attention because LTα also partners with LTβ to generate membrane-tethered LTαβ2that promotes tertiary lymphoid tissue—another feature of Crohn’s disease. We hypothesized that B cell-derived LTαβ2would critically affect ileitis in TNFΔARE+/−mice. However, whereas deleting LTβ in B cells was essential for tertiary lymphoid tissue, disease pathology was minimally affected. By contrast, loss of B cell-derived LTα increased intestinal permeability, shrunk the pool of IgA+ileal plasma cells, elevated cytokines and prompted weight loss, including loss of muscle mass—a systemic feature of Crohn’s disease. Neutralizing antibodies to LTα3strongly augmented the cachexic-like effects of TNF. Thus, B cell-produced LTαβ2and LTα3have distinct roles in ileitis, with the role of LTα3unexpectedly protective through counterbalancing TNF. Crohn's disease Tumour-necrosis factors
N Nature Immunology · Sep 05, 2025 Type A cholesterol-dependent cytolysins translocate to thetrans-Golgi network for NLRP3 inflammasome activation Cholesterol-dependent cytolysins (CDCs) constitute the largest group of pore-forming toxins and serve as critical virulence factors for diverse pathogenic bacteria. Several CDCs are known to activate the NLRP3 inflammasome, although the mechanisms are unclear. Here we discovered that multiple CDCs, which we referred to as type A CDCs, were internalized and translocated to the trans-Golgi network (TGN) to remodel it into a platform for NLRP3 activation through a unique peeling membrane mechanism. Potassium efflux was dispensable for CDC-mediated TGN remodeling and NLRP3 recruitment, but was required for the recruitment of the downstream adaptor ASC. In contrast, desulfolysin, which we referred to as type B CDC, was not internalized or translocated to the TGN due to its distinct C-terminal domain 4, despite potent pore formation on the plasma membrane, and hence could not activate NLRP3. Our discoveries uncovered the ability of CDCs to directly remodel an intracellular organelle for inflammatory response. Chen and colleagues show that type A cholesterol-dependent cytolysins, a group of bacteria pore-forming toxins, translocate to the trans-Golgi network to remodel it into a platform for NLRP3 activation. Bacteria NOD-like receptors
N Nature Immunology · Aug 29, 2025 E3 ligase RAD18 targets phosphorylated IRF3 to terminateIFNB1transcription The transcription factor interferon regulatory factor 3 (IRF3) initiates type I interferon transcription, which is required for host defense. Here, we identify RAD18 as a central E3 ubiquitin ligase that selectively targets phosphorylated IRF3 (p-IRF3) for autophagic degradation. RAD18 specifically promotes the dissociation of p-IRF3 from theIFNBpromoter and in turn terminates its transcriptional activity. Mechanistically, RAD18 binds the p-IRF3 dimer located on theIFNBpromoter and triggers K63 polyubiquitylation of p-IRF3 at Lys 193. The ubiquitylated p-IRF3 dimer consequently dissociates from theIFNBpromoter, translocates out of the nucleus and undergoes OPTN-mediated autophagic degradation.Rad18fl/flLysm-cremice resist lethal vesicular stomatitis virus infection in vivo due to IFNβ overproduction. In H1N1-infected human macrophages or monocytes from individuals with active systemic lupus erythematosus, RAD18 protein levels negatively correlate with p-IRF3 andIFNB1mRNA levels. Thus, RAD18 functions as a break to terminate IRF3-drivenIFNB1transcription and may be a potential therapeutic target for RNA virus infection or autoimmune diseases. Autophagy Innate immunity Ubiquitin ligases Viral infection
N Nature Immunology · Aug 29, 2025 Single-cell atlas of human liver and blood immune cells across fatty liver disease stages reveals distinct signatures linked to liver dysfunction and fibrogenesis Immune cells play a central yet poorly understood role in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASLD/MASH), a global cause of liver disease with limited treatment. Limited access to human livers and lack of studies across MASLD/MASH stages thwart identification of stage-specific immunological targets. Here we provide a unique single-cell RNA sequencing atlas of paired peripheral blood and liver fine-needle aspirates from a full-spectrum MASLD/MASH human cohort. Our findings included heightened immunoregulatory programs with MASH progression, such as enriched hepatic regulatory T cells, monocytic myeloid-derived suppressor cells,TREM2+S100A9+macrophages andS100hiHLAlotype 2 conventional dendritic cells. Hepatic cytotoxic T cell functions increased with inflammation, but decreased with fibrosis, while acquiring an exhausted signature, whereas natural killer cell-driven toxicity intensified. Our dataset proposes immunological mechanisms for increased fibrogenesis and vulnerability to liver cancer and infections in MASH and provides a basis for a deeper understanding of human immunological dysfunction in chronic liver disease and a roadmap to new targeted therapies. Chronic inflammation Immunology Immunopathogenesis Inflammatory diseases
N Nature Immunology · Aug 27, 2025 TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors TCR-T cells are T cells engineered to express a specific T cell receptor. Here the authors present a TCR-T cell that targets CTNNB1-S37F, corresponding to a shared cancer driver mutation. This immunotherapy killed solid tumors when applied to a patient-derived xenograft model in mice.
N Nature Immunology · Aug 27, 2025 Simultaneous STING and lymphotoxin-β receptor activation induces B cell responses in tertiary lymphoid structures to potentiate antitumor immunity Sawada et al. show simultaneous activation of the STING and lymphotoxin beta receptor signaling induces B cell-activating germinal center responses within tumor environment and enhances antitumor responses.
N Nature Immunology · Aug 27, 2025 Pre-TCR-targeted immunotherapy for T cell acute lymphoblastic leukemia The authors identify pre-TCR as a key biomarker and therapeutic target in T-ALL. Targeting it with an anti-pTα antibody–drug conjugate inhibits leukemia-initiating cells and tumor growth in mice, offering promise for relapsed/refractory T-ALL treatment.
N Nature Immunology · Aug 22, 2025 SATB1 is a key regulator of quiescence in stem-like CD8+T cells Stem-like progenitor CD8+T (TPRO) cells sustain cytotoxic immunity during chronic infection and cancer through quiescence, multipotency and self-renewal, hallmarks shared with memory T cells. However, how these properties are maintained under persistent antigen stimulation remains unclear. Here we identify the genomic organizer SATB1 as selectively enriched in both TPROand memory CD8+T cells. Given its role in promoting quiescence in hematopoietic stem cells, we hypothesized that SATB1 supports CD8+T cell stemness. Using CD8+T cell-specific CRISPR deletion of theSatb1gene, we show that SATB1 is essential for maintaining TPROcells during chronic lymphocytic choriomeningitis virus infection and for memory CD8+T cell formation during acute infection. Multi-omic profiling revealed that SATB1 regulates the chromatin accessibility, transcriptional activity and genome architecture of stemness-associated genes includingTcf7,Bach2andMyb. These findings reveal a critical role for SATB1 in preserving the transcriptional and epigenetic programs that sustain the stem-like state of antigen-specific CD8+T cells. CD8-positive T cells Lymphocyte differentiation
N Nature Immunology · Aug 18, 2025 Loss of YTHDF2 enhances Th9 programming and CAR-Th9 cell antitumor efficacy CD4+T cells differentiate into various subsets, including T helper 1 (Th1), Th2, Th9, Th17 and regulatory T (Treg) cells, which are essential for immune responses and cancer immunotherapy. However, the role of RNAN6-methyladenosine (m6A) modification in this differentiation is unclear. Here we show that YTHDF2, an important m6A reader protein known to destabilize m6A-modified mRNA, negatively regulates Th9 cell differentiation. Ablation ofYthdf2in both mouse and human naive CD4+T cells promotes Th9 differentiation by stabilizingGata3andSmad3mRNA under interleukin-4 (IL-4) and transforming growth factor β (TGF-β) signaling, respectively.Ythdf2-deficient Th9 cells produce increased amounts of IL-9 and IL-21, leading to increased tumor infiltration and cytotoxicity by CD8+T cells and natural killer (NK) cells, thereby improving antitumor activity compared with wild-type Th9 cells. Moreover, YTHDF2 depletion in CAR-Th9 cells enhances their immune activation, reduces their terminal differentiation and augments their antitumor efficacy. Targeting YTHDF2 is thereby a promising strategy to enhance Th9 and CAR-Th9 cell-based cancer immunotherapies. Cancer immunotherapy CD4-positive T cells Lymphocyte differentiation
N Nature Immunology · Aug 15, 2025 CGRP-related neuropeptide adrenomedullin 2 promotes tissue-protective ILC2 responses and limits intestinal inflammation Neuro–immune circuits regulate innate and adaptive immunity at barrier surfaces. However, the differential impact of these circuits on proinflammatory versus tissue-protective responses remains poorly defined. We demonstrate that enteric neurons produce calcitonin gene-related peptide-related adrenomedullin 2 (ADM2) and identify a previously unrecognized role for the ADM2 pathway in promoting intestinal tissue-protective functions of group 2 innate lymphoid cells (ILC2s). Genomic or ILC2-intrinsic deletion of ADM2 receptor subunits resulted in a significant reduction in tissue-protective ILC2 responses, defective amphiregulin (AREG) production and increased susceptibility to intestinal damage and inflammation. Conversely, therapeutic delivery of recombinant ADM2 elicited tissue-protective AREG+ILC2s and limited intestinal inflammation. Expression of genes encoding human ADM2 receptor (CALCRLandRAMP3) was altered in participants with inflammatory bowel diseases and associated with reduced expression ofAREGin ILC2s. Collectively, these findings identify that the ADM2–ADM2 receptor pathway can promote tissue-protective functions of ILC2s in the context of intestinal damage and inflammation. Innate lymphoid cells Mucosal immunology Neuroimmunology
