Pub Date : 2025-12-09DOI: 10.1016/j.immuni.2025.11.012
Qiang Dong, Chengcheng Jin
TET2 mutations can drive clonal hematopoiesis (CH), but their impact on tumor immunity remains unresolved. Recently in Cancer Cell, Herbrich et al. reported that TET2-mutant CH reprograms tumor-associated macrophages to enhance antigen presentation and immune-checkpoint therapy efficacy in solid tumors.
Pub Date : 2025-12-09Epub Date: 2025-10-20DOI: 10.1016/j.immuni.2025.09.019
Dario Priem, Jon Huyghe, Barbara Gilbert, Simon Verdonck, Tom Delanghe, Bruno Verstraeten, Esther Hoste, Peter Vandenabeele, Jonathan Maelfait, Geert van Loo, Mathieu J M Bertrand
Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine with pathologic roles in chronic inflammatory and autoimmune disorders. The mechanisms by which TNF sensing drives the pathogenesis of these diseases are not fully understood. We previously showed that the lack of the autophagic lipid scramblase ATG9A in mouse keratinocytes leads to severe dermatitis and systemic inflammation, with features resembling human skin disorders. We now demonstrate that the disease is initiated by TNF but caused by cGAS/STING-dependent type I interferon (IFN) production and subsequent ZBP1-dependent apoptosis and necroptosis. ATG9A prevented the pathogenesis of the disease by engaging both light-chain 3 (LC3)-dependent and -independent autophagy. These results uncover an additional pathological arm of TNF signaling, opening avenues for alternative therapeutic interventions for TNF-driven diseases. Moreover, this study reveals another pathophysiological function of LC3-independent autophagy in restraining type I IFN production, which triggers the development or exacerbation of an interferonopathy in mice and humans.
{"title":"ATG9A-mediated autophagy prevents inflammatory skin disease by limiting TNFR1-driven STING activation and ZBP1-dependent cell death.","authors":"Dario Priem, Jon Huyghe, Barbara Gilbert, Simon Verdonck, Tom Delanghe, Bruno Verstraeten, Esther Hoste, Peter Vandenabeele, Jonathan Maelfait, Geert van Loo, Mathieu J M Bertrand","doi":"10.1016/j.immuni.2025.09.019","DOIUrl":"10.1016/j.immuni.2025.09.019","url":null,"abstract":"<p><p>Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine with pathologic roles in chronic inflammatory and autoimmune disorders. The mechanisms by which TNF sensing drives the pathogenesis of these diseases are not fully understood. We previously showed that the lack of the autophagic lipid scramblase ATG9A in mouse keratinocytes leads to severe dermatitis and systemic inflammation, with features resembling human skin disorders. We now demonstrate that the disease is initiated by TNF but caused by cGAS/STING-dependent type I interferon (IFN) production and subsequent ZBP1-dependent apoptosis and necroptosis. ATG9A prevented the pathogenesis of the disease by engaging both light-chain 3 (LC3)-dependent and -independent autophagy. These results uncover an additional pathological arm of TNF signaling, opening avenues for alternative therapeutic interventions for TNF-driven diseases. Moreover, this study reveals another pathophysiological function of LC3-independent autophagy in restraining type I IFN production, which triggers the development or exacerbation of an interferonopathy in mice and humans.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2972-2988.e6"},"PeriodicalIF":26.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145345081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.immuni.2025.11.016
Brydie R. Huckestein, Paul G. Thomas
Lung-resident memory CD8+ T cells coordinate rapid antiviral defense mechanisms across lung compartments to quicky limit viral replication and spread. In this issue of Immunity, Mattingly et al. demonstrate the importance of CD8+ Trm cell-derived interferon-γ in epithelial reprogramming for barrier defense in humans.
{"title":"Memories are I(F)N-credibly protective","authors":"Brydie R. Huckestein, Paul G. Thomas","doi":"10.1016/j.immuni.2025.11.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.016","url":null,"abstract":"Lung-resident memory CD8<sup>+</sup> T cells coordinate rapid antiviral defense mechanisms across lung compartments to quicky limit viral replication and spread. In this issue of <em>Immunity</em>, Mattingly et al. demonstrate the importance of CD8<sup>+</sup> Trm cell-derived interferon-γ in epithelial reprogramming for barrier defense in humans.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"43 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.immuni.2025.11.011
Christophe Benoist, Dario A.A. Vignali, Richard A. Flavell, Diane Mathis
The seminal discoveries that established the role of regulatory T cells in immunological tolerance were recognized by this year’s Nobel Prize in Physiology or Medicine. We present here the unfolding of the Treg story, the players involved at various stages, and the explosive growth of knowledge about this fascinating cell population.
{"title":"The history and promise of Treg cells","authors":"Christophe Benoist, Dario A.A. Vignali, Richard A. Flavell, Diane Mathis","doi":"10.1016/j.immuni.2025.11.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.011","url":null,"abstract":"The seminal discoveries that established the role of regulatory T cells in immunological tolerance were recognized by this year’s Nobel Prize in Physiology or Medicine. We present here the unfolding of the Treg story, the players involved at various stages, and the explosive growth of knowledge about this fascinating cell population.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.immuni.2025.11.008
Ying Feng, Francis Ka-Ming Chan
Tumor necrosis factor (TNF), type I interferons (IFNs), and autophagy are important biological processes, but their interactions in inflammation have not been explored. In this issue of Immunity, Priem et al. reveal that ATG9A-mediated autophagy curbs skin inflammation by suppressing STING activation and Z-DNA binding protein 1 (ZBP1)-dependent cell death.
{"title":"Skin deep: Unconventional autophagy eats away TNF-driven skin inflammation.","authors":"Ying Feng, Francis Ka-Ming Chan","doi":"10.1016/j.immuni.2025.11.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.008","url":null,"abstract":"<p><p>Tumor necrosis factor (TNF), type I interferons (IFNs), and autophagy are important biological processes, but their interactions in inflammation have not been explored. In this issue of Immunity, Priem et al. reveal that ATG9A-mediated autophagy curbs skin inflammation by suppressing STING activation and Z-DNA binding protein 1 (ZBP1)-dependent cell death.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"58 12","pages":"2920-2922"},"PeriodicalIF":26.3,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145722613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.immuni.2025.11.002
Clara Alice Musi, Diego Gomez-Nicola
The initial responses of microglia to neuronal stress or altered network activity are poorly characterized. Xie and colleagues show that during TDP-43-related neurodegeneration, microglia detect early neuronal hyperactivity and transition into a distinct rod-shaped state. This study uncovers a microglial state that precedes overt neuronal loss, shedding new light on the earliest stages of neurodegeneration.
{"title":"Shape-shifting microglia respond to neuronal hyperexcitability","authors":"Clara Alice Musi, Diego Gomez-Nicola","doi":"10.1016/j.immuni.2025.11.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.002","url":null,"abstract":"The initial responses of microglia to neuronal stress or altered network activity are poorly characterized. Xie and colleagues show that during TDP-43-related neurodegeneration, microglia detect early neuronal hyperactivity and transition into a distinct rod-shaped state. This study uncovers a microglial state that precedes overt neuronal loss, shedding new light on the earliest stages of neurodegeneration.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"20 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aberrant tissue infiltration by activated CD4+ T cells is a central driver of autoimmunity, yet the molecular checkpoints governing antigen-specific T cell ingress remain poorly defined. We found that the transcription factor SUB1 was selectively upregulated in CD4+ T cells from individuals with autoimmune diseases. SUB1 expression was induced by the T cell receptor (TCR)-interferon regulatory factor 4 (IRF4) transcription factor axis. Conditional deletion of Sub1 in T cells reduced the expression of migration regulator dedicator of cytokinesis 2 (DOCK2), inhibited Rac-dependent actin polymerization and T cell motility, and prevented the onset of experimental autoimmune encephalomyelitis. Mechanistically, SUB1 underwent liquid-liquid phase separation to form biomolecular condensates that opened chromatin at the Junb and Dock2 loci. It then directly trans-activated Junb transcription and partnered with JUNB to amplify Dock2 transcription. Therefore, SUB1 is a critical gatekeeper of pathogenic T cell trafficking, and by linking TCR signaling to cytoskeletal remodeling, the TCR-SUB1-DOCK2 axis emerges as a tractable, migration-focused therapeutic target in autoimmune disorders.
{"title":"The TCR-SUB1-DOCK2 axis promotes autoimmunity by driving pathogenic CD4+ T cell tissue infiltration","authors":"Xiaoxue Li, Wenhua Liang, Weifang Wang, Eilon Sherman, Keling Huang, Feng Wang","doi":"10.1016/j.immuni.2025.11.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.009","url":null,"abstract":"Aberrant tissue infiltration by activated CD4<sup>+</sup> T cells is a central driver of autoimmunity, yet the molecular checkpoints governing antigen-specific T cell ingress remain poorly defined. We found that the transcription factor SUB1 was selectively upregulated in CD4<sup>+</sup> T cells from individuals with autoimmune diseases. SUB1 expression was induced by the T cell receptor (TCR)-interferon regulatory factor 4 (IRF4) transcription factor axis. Conditional deletion of <em>Sub1</em> in T cells reduced the expression of migration regulator dedicator of cytokinesis 2 (DOCK2), inhibited Rac-dependent actin polymerization and T cell motility, and prevented the onset of experimental autoimmune encephalomyelitis. Mechanistically, SUB1 underwent liquid-liquid phase separation to form biomolecular condensates that opened chromatin at the <em>Junb</em> and <em>Dock2</em> loci. It then directly <em>trans</em>-activated <em>Junb</em> transcription and partnered with JUNB to amplify <em>Dock2</em> transcription. Therefore, SUB1 is a critical gatekeeper of pathogenic T cell trafficking, and by linking TCR signaling to cytoskeletal remodeling, the TCR-SUB1-DOCK2 axis emerges as a tractable, migration-focused therapeutic target in autoimmune disorders.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"4 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-09DOI: 10.1016/j.immuni.2025.11.017
Gabrielle R. Berman, Carla R. Nowosad
IgA plasma cells are the most abundant antibody-secreting reservoir in the body, yet details of their origin and behavior remain elusive. In this issue of Immunity, Simons et al. and Siniscalco et al. offer insights into IgA plasma cell dynamics during homeostasis and immunization.
{"title":"Intestinal plasma cells get in formation","authors":"Gabrielle R. Berman, Carla R. Nowosad","doi":"10.1016/j.immuni.2025.11.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.017","url":null,"abstract":"IgA plasma cells are the most abundant antibody-secreting reservoir in the body, yet details of their origin and behavior remain elusive. In this issue of <em>Immunity</em>, Simons et al. and Siniscalco et al. offer insights into IgA plasma cell dynamics during homeostasis and immunization.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"141 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is critical in innate immunity. Recent research has highlighted the importance of phosphatidylinositol 4-phosphate (PI4P) signaling within the Golgi apparatus for STING activation. However, the exact molecular mechanisms by which PI4P regulates STING have remained unclear. Here, we report the activation mechanism of STING triggered by PI4P and a chemical STING agonist, GNE-6468. Utilizing cryoelectron microscopy, we determined that GNE-6468 bound to a distinct pocket within the STING transmembrane (TM) domain, promoting outward movements of the STING TM3 helix without altering the conformation of the ligand-binding domain. Notably, we provided structural insights into STING bound to both PI4P and GNE-6468, and they collectively induced STING oligomerization and STING-mediated immune responses. Functional assays further confirmed that the interactions among STING, PI4P, and GNE-6468 were essential for STING activation. Collectively, these results demonstrate that PI4P and GNE-6468 cooperatively bind STING to activate its signaling, highlighting its therapeutic potential.
{"title":"A chemical agonist and the Golgi-resident lipid PI4P activate STING by inducing transmembrane helix rearrangement","authors":"Jing Han, Shuhao Zhang, Yanfei Hou, Yi Wang, Zhengyin Zhang, Jiaming Yang, Yifang Xu, Zexu Peng, Hang Yin, Kehong Chen, Xiangyu Liu, Conggang Zhang","doi":"10.1016/j.immuni.2025.11.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.004","url":null,"abstract":"The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is critical in innate immunity. Recent research has highlighted the importance of phosphatidylinositol 4-phosphate (PI4P) signaling within the Golgi apparatus for STING activation. However, the exact molecular mechanisms by which PI4P regulates STING have remained unclear. Here, we report the activation mechanism of STING triggered by PI4P and a chemical STING agonist, GNE-6468. Utilizing cryoelectron microscopy, we determined that GNE-6468 bound to a distinct pocket within the STING transmembrane (TM) domain, promoting outward movements of the STING TM3 helix without altering the conformation of the ligand-binding domain. Notably, we provided structural insights into STING bound to both PI4P and GNE-6468, and they collectively induced STING oligomerization and STING-mediated immune responses. Functional assays further confirmed that the interactions among STING, PI4P, and GNE-6468 were essential for STING activation. Collectively, these results demonstrate that PI4P and GNE-6468 cooperatively bind STING to activate its signaling, highlighting its therapeutic potential.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"115 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.immuni.2025.11.006
Takahiro Yamada, Noah W. Palm
{"title":"A host-centric view of the microbiota metabolome","authors":"Takahiro Yamada, Noah W. Palm","doi":"10.1016/j.immuni.2025.11.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.006","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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