ImmunityPub Date : 2025-10-21DOI: 10.1016/j.immuni.2025.09.018
Pinar Cakmak, Jennifer H Lun, Aakanksha Singh, Jadranka Macas, Jonathan Schupp, Jonas Schuck, Zeina Mahmoud, Miriam Köhler, Tatjana Starzetz, Michael C Burger, Eike Steidl, Lucie Marie Hasse, Elke Hattingen, Karl H Plate, Yvonne Reiss, Katharina Imkeller
{"title":"Spatial immune profiling defines a subset of human gliomas with functional tertiary lymphoid structures.","authors":"Pinar Cakmak, Jennifer H Lun, Aakanksha Singh, Jadranka Macas, Jonathan Schupp, Jonas Schuck, Zeina Mahmoud, Miriam Köhler, Tatjana Starzetz, Michael C Burger, Eike Steidl, Lucie Marie Hasse, Elke Hattingen, Karl H Plate, Yvonne Reiss, Katharina Imkeller","doi":"10.1016/j.immuni.2025.09.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.018","url":null,"abstract":"<p><p>Adult-type diffuse gliomas, the most common primary brain tumors, respond poorly to immune-based therapies and are considered immunologically \"cold\" tumors. Here, we examined the features and clinical relevance of glioma intratumoral tertiary lymphoid structures (TLSs) using spatial transcriptome and proteome profiling. In a cohort of 642 gliomas, TLSs were present in 15% of tumors and associated with a remodeled perivascular space and spatial redistribution of extracellular matrix components. Three distinct TLS subtypes could be defined based on differing cellular composition and immune activity. While all subtypes lacked classical germinal center architecture, certain TLSs exhibited features of dynamic immune functions, including clonal T and B cell expansion, generation of IgA⁺ and IgG⁺ plasma cells, and dendritic cell-T cell interactions. The presence of TLSs with active immune response features correlated with improved overall survival. Thus, a functional adaptive immune response is detectable in some gliomas, with implications for stratification and treatment.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":26.3,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145345140","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}
ImmunityPub 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
{"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":"https://doi.org/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":""},"PeriodicalIF":26.3,"publicationDate":"2025-10-20","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}
ImmunityPub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.015
Zhaoyu Lin, Hai-Bin Ruan
{"title":"Cutting the Gordian knot: Untangling gasdermin C from pyroptosis","authors":"Zhaoyu Lin, Hai-Bin Ruan","doi":"10.1016/j.immuni.2025.09.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.015","url":null,"abstract":"Membrane targeting and pore formation of gasdermin C are facilitated by its proteolytic cleavage. In this issue of <em>Immunity</em>, Pandey et al. show how cathepsin S cleaves intestinal epithelial gasdermin C to amplify type 2 immune responses.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"24 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283463","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}
ImmunityPub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.017
Sigrun Stulz, Georg Gasteiger
{"title":"Resident memory T cells call the shots in tissue immunity","authors":"Sigrun Stulz, Georg Gasteiger","doi":"10.1016/j.immuni.2025.09.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.017","url":null,"abstract":"Vaccines that induce immunity in tissues are urgently needed. In this issue of <em>Immunity</em>, Joag et al. demonstrate that systemic vaccination of primates induces tissue-resident CD8<sup>+</sup> T cells in numerous organs that can activate antiviral responses by stromal, parenchymal, and immune cells.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"11 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283465","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}
ImmunityPub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.010
Jake A. Gertie, Hachung Chung
{"title":"Alzheimer’s alphabet soup: Find the letters “Z-DNA-ZBP1-RIPK1”","authors":"Jake A. Gertie, Hachung Chung","doi":"10.1016/j.immuni.2025.09.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.010","url":null,"abstract":"Neuroinflammation contributes to Alzheimer’s disease (AD), but the molecules and pathways that initiate inflammation are unclear. In this issue of <em>Immunity</em>, Song et al. demonstrate that ZBP1-RIPK1 signaling in microglia can drive AD, wherein ZBP1 is activated by left-handed Z-DNA leaking from mitochondria, presenting new molecular targets for AD therapeutics.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"43 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283468","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}
ImmunityPub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.005
Adrian Straub, Zahra Abedi, Dirk H. Busch, Veit R. Buchholz
{"title":"Nurture over nature in fate decisions of antigen-specific CD8+ T cell clones from an endogenous repertoire","authors":"Adrian Straub, Zahra Abedi, Dirk H. Busch, Veit R. Buchholz","doi":"10.1016/j.immuni.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.005","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>Abdullah et al.<sup>1</sup> recently set out to gauge the influence of T cell receptor (TCR)-intrinsic vs. -extrinsic factors on memory vs. effector fate decisions of CD8<sup>+</sup> T cells. They concluded that “a majority of TCR clonotypes were highly biased toward memory or effector fate,” and that “TCR intrinsic biases […] were dominant over environmental cues.” We argue that these conclusions cannot be drawn based on the authors’ limited clonotypic data and are strongly opposed by our own observation of highly</section></section><section><section><h2>Acknowledgments</h2>The ultra-deep H2-K<sup>b</sup>/SIINFEKL-specific TCR library was created as part of the MATCHMAKERS team, supported by the Cancer Grand Challenges partnership financed by <span>CRUK</span> (CGCATF-2023/100002) and the <span>National Cancer Institute</span> (1OT2CA297204-01). A.S., Z.A., and D.H.B. are members of the MATCHMAKERS team. The work was further funded by SFB-TRR 338/1 2021- 452881907 (project A01 [D.H.B.] and project B02 [V.R.B.]) and the <span>European Research Council</span> (starting grant 949719 SCIMAP to V.R.B.).</section></section><section><section><h2>Declaration of interests</h2>The authors declare no competing interests.</section></section>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"81 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283462","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}
ImmunityPub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.009
Vineet Joag, Benjamin N. Bimber, Clare F. Quarnstrom, Venkata S. Bollimpelli, Jason M. Schenkel, Kathryn A. Fraser, Mario Bertogliat, Andrew G. Soerens, J. Michael Stolley, Stephen D. O’Flanagan, Pamela C. Rosato, Noah V. Gavil, Marco Künzli, Jason S. Mitchell, Traci Legere, Sherrie Jean, Amit A. Upadhyay, C. Yong Kang, James Gibbs, Jonathan W. Yewdell, David Masopust
{"title":"Primate resident memory T cells activate humoral and stromal immunity","authors":"Vineet Joag, Benjamin N. Bimber, Clare F. Quarnstrom, Venkata S. Bollimpelli, Jason M. Schenkel, Kathryn A. Fraser, Mario Bertogliat, Andrew G. Soerens, J. Michael Stolley, Stephen D. O’Flanagan, Pamela C. Rosato, Noah V. Gavil, Marco Künzli, Jason S. Mitchell, Traci Legere, Sherrie Jean, Amit A. Upadhyay, C. Yong Kang, James Gibbs, Jonathan W. Yewdell, David Masopust","doi":"10.1016/j.immuni.2025.09.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.009","url":null,"abstract":"CD8<sup>+</sup> resident memory T (Trm) cells comprise a small population of frontline sentinels compared with the large tissues they surveil, making outsized contributions to immune protection from infection. Here, we interrogated mechanisms of Trm cell function in primates. Intravenous immunization of macaques with a simian immunodeficiency virus (SIV)-gag-containing heterologous prime-boost-boost vaccine established memory T cells in >30 tissues, including visceral and mucosal compartments. Upon <em>in vivo</em> reactivation in the reproductive tract, antigen-sensing CD8<sup>+</sup> Trm activated local stromal, parenchymal, and innate and adaptive immune cells. Stromal and parenchymal cells accentuated leukocyte migration and antiviral defenses. B and plasma cells mobilized into the vaginal mucosa, and bloodborne CD4<sup>+</sup> T cells were recruited and adopted a host-defense program. Our findings demonstrate that systemic vaccination promotes a Trm cell response in barrier compartments and that Trm cells repurpose abundant neighboring stromal, parenchymal, and immune cells to amplify alarm signals and activate diverse host defenses.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"120 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283789","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}
ImmunityPub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.006
Leena Abdullah, Joshua J. Obar, Yina H. Huang
{"title":"Reply to nurture over nature in fate decisions of antigen-specific CD8+ T cell clones from an endogenous repertoire","authors":"Leena Abdullah, Joshua J. Obar, Yina H. Huang","doi":"10.1016/j.immuni.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.006","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>Upon activation, individual CD8<sup>+</sup> clones decide between effector and memory T cell fates by integrating intrinsic T cell receptor (TCR) signals or “nature” and extrinsic signals from co-stimulatory ligands and inflammatory cytokines or “nurture”. The collective antigen-specific CD8<sup>+</sup> T cell response is composed of differential fate decisions made by ∼100–1,000 individual clones. Several models describe how variations in nature drive effector vs. memory T cell differentiation, including the</section></section><section><section><h2>Acknowledgments</h2>This work was supported in part by the <span>National Institutes of Health</span> (NIH) grant <!-- -->R01-AI131975<!-- --> to Y.H.H.; Tom and Susan Stepp to Y.H.H.; <span>Prouty Developmental grant</span> to Y.H.H.; <span>NIH</span> grants <!-- -->P20-GM130454<!-- -->, <!-- -->S10-OD025235<!-- -->, and <!-- -->S10-OD030242<!-- -->, which support the single-cell genomics core; and <span>NIH</span> grant <!-- -->P30-CA023108<!-- -->, which supports the <span>Dartmouth Cancer Center’s flow cytometry</span> (RRID: <span>SCR_019165</span>) and genomics (RRID: <span>SCR_021293</span>) shared resources.</section></section><section><section><h2>Author contributions</h2>L.A. and Y.H.H. wrote the original manuscript. J.J.O. provided feedback on the final manuscript.</section></section><section><section><h2>Declaration of interests</h2>The authors declare no competing interests.</section></section>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"3 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283466","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}
ImmunityPub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.016
Alexander J. Wesolowski, Rahul Roychoudhuri
{"title":"Burning the candle at both ends: ROS-mediated telomere damage drives T cell dysfunction","authors":"Alexander J. Wesolowski, Rahul Roychoudhuri","doi":"10.1016/j.immuni.2025.09.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.016","url":null,"abstract":"T cells need reactive oxygen species (ROS) for activation and memory formation, yet excessive ROS can drive dysfunction. Rivadeneira et al. show that chronic T cell activation in tumors exposes telomeres to damaging mitochondrial ROS, contributing to T cell dysfunction.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"19 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283464","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}
ImmunityPub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.013
Danae N. Mitchell, Julie A. Siegenthaler
{"title":"Fibroblasts are not so scar-y in brain injury","authors":"Danae N. Mitchell, Julie A. Siegenthaler","doi":"10.1016/j.immuni.2025.09.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.013","url":null,"abstract":"Fibroblasts and immune cells robustly respond to brain injuries and form a persistent “scar.” In a recent issue of <em>Nature</em>, Ewing-Crystal et al. report that fibroblasts have dynamic states that modulate neuroinflammatory responses to brain injury, vital to limiting initial injury and promoting repair.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"12 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145283467","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}