Pub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.005
Adrian Straub, Zahra Abedi, Dirk H. Busch, Veit R. Buchholz
Section snippets
Main text
Abdullah et al.1 recently set out to gauge the influence of T cell receptor (TCR)-intrinsic vs. -extrinsic factors on memory vs. effector fate decisions of CD8+ 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
Acknowledgments
The ultra-deep H2-Kb/SIINFEKL-specific TCR library was created as part of the MATCHMAKERS team, supported by the Cancer Grand Challenges partnership financed by CRUK (CGCATF-2023/100002) and the National Cancer Institute (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 European Research Council (starting grant 949719 SCIMAP to V.R.B.).
{"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}
Pub 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
CD8+ 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 in vivo reactivation in the reproductive tract, antigen-sensing CD8+ 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+ 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.
{"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}
Pub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.006
Leena Abdullah, Joshua J. Obar, Yina H. Huang
Section snippets
Main text
Upon activation, individual CD8+ 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+ 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
Acknowledgments
This work was supported in part by the National Institutes of Health (NIH) grant R01-AI131975 to Y.H.H.; Tom and Susan Stepp to Y.H.H.; Prouty Developmental grant to Y.H.H.; NIH grants P20-GM130454, S10-OD025235, and S10-OD030242, which support the single-cell genomics core; and NIH grant P30-CA023108, which supports the Dartmouth Cancer Center’s flow cytometry (RRID: SCR_019165) and genomics (RRID: SCR_021293) shared resources.
Author contributions
L.A. and Y.H.H. wrote the original manuscript. J.J.O. provided feedback on the final manuscript.
{"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}
Pub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.016
Alexander J. Wesolowski, Rahul Roychoudhuri
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.
{"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}
Pub Date : 2025-10-14DOI: 10.1016/j.immuni.2025.09.013
Danae N. Mitchell, Julie A. Siegenthaler
Fibroblasts and immune cells robustly respond to brain injuries and form a persistent “scar.” In a recent issue of Nature, 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.
{"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}
Pub Date : 2025-10-09DOI: 10.1016/j.immuni.2025.09.014
Ezra T. Bekkering, Randy Yoo, Sophia Hailemariam, Fabian Heide, Danton Ivanochko, Matthew Jackman, Nicholas I. Proellochs, Rianne Stoter, Geert-Jan van Gemert, Ayana Maeda, Takaaki Yuguchi, Oscar T. Wanders, Renate C. van Daalen, Maartje R. Inklaar, Carolina M. Andrade, Pascal W.T.C. Jansen, Michiel Vermeulen, Teun Bousema, Eizo Takashima, John L. Rubinstein, Jean-Philippe Julien
The Pfs230:Pfs48/45 complex forms the basis for leading malaria transmission-blocking vaccine candidates, yet little is known about its molecular assembly. Here, we used cryo-electron microscopy to elucidate the structure of the endogenous Pfs230:Pfs48/45 complex bound to six transmission-blocking antibodies. Our structure revealed that Pfs230 consists of multiple domain clusters rigidified by interactions mediated through insertion domains. Membrane-anchored Pfs48/45 formed a disk-like structure, interacting with a short C-terminal peptide on Pfs230 that was critical for Pfs230 membrane-retention in vivo. Membrane retention through this interaction was not essential for transmission to mosquitoes, suggesting that complex disruption is not a mode of action for transmission-blocking antibodies. Analyses of Pfs48/45- and Pfs230-targeted antibodies identified conserved epitopes on the Pfs230:Pfs48/45 complex and provided a structural paradigm for complement-dependent activity of Pfs230-targeting antibodies. Altogether, the antibody-bound Pfs230:Pfs48/45 structure improves our molecular understanding of this biological complex, informing the development of next-generation Plasmodium falciparum transmission-blocking interventions.
{"title":"Cryo-EM structure of endogenous Pfs230:Pfs48/45 complex with six antibodies reveals mechanisms of malaria transmission-blocking activity","authors":"Ezra T. Bekkering, Randy Yoo, Sophia Hailemariam, Fabian Heide, Danton Ivanochko, Matthew Jackman, Nicholas I. Proellochs, Rianne Stoter, Geert-Jan van Gemert, Ayana Maeda, Takaaki Yuguchi, Oscar T. Wanders, Renate C. van Daalen, Maartje R. Inklaar, Carolina M. Andrade, Pascal W.T.C. Jansen, Michiel Vermeulen, Teun Bousema, Eizo Takashima, John L. Rubinstein, Jean-Philippe Julien","doi":"10.1016/j.immuni.2025.09.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.014","url":null,"abstract":"The Pfs230:Pfs48/45 complex forms the basis for leading malaria transmission-blocking vaccine candidates, yet little is known about its molecular assembly. Here, we used cryo-electron microscopy to elucidate the structure of the endogenous Pfs230:Pfs48/45 complex bound to six transmission-blocking antibodies. Our structure revealed that Pfs230 consists of multiple domain clusters rigidified by interactions mediated through insertion domains. Membrane-anchored Pfs48/45 formed a disk-like structure, interacting with a short C-terminal peptide on Pfs230 that was critical for Pfs230 membrane-retention <em>in vivo</em>. Membrane retention through this interaction was not essential for transmission to mosquitoes, suggesting that complex disruption is not a mode of action for transmission-blocking antibodies. Analyses of Pfs48/45- and Pfs230-targeted antibodies identified conserved epitopes on the Pfs230:Pfs48/45 complex and provided a structural paradigm for complement-dependent activity of Pfs230-targeting antibodies. Altogether, the antibody-bound Pfs230:Pfs48/45 structure improves our molecular understanding of this biological complex, informing the development of next-generation <em>Plasmodium falciparum</em> transmission-blocking interventions.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"11 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145247582","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 : 2025-10-03DOI: 10.1016/j.immuni.2025.09.012
Peter Libby, Oliver Soehnlein
Inflammatory pathways operate at all stages of atherosclerosis. These processes are driven by risk factors and other stimuli that can spark inflammation by eliciting misdirected responses of intrinsic vascular cells and leukocytes, culminating in lesion initiation, progression, and complication. Continuing dissection of the key underlying inflammatory mechanisms with increasingly sophisticated tools has inspired successful clinical trials and enabled translation to the clinic. Here, we review the mechanistic understanding of the etiology and progression of atherosclerosis. We discuss how cardiovascular risk factors converge at the level of the bone marrow to perturb hematopoiesis, yielding output with a pro-inflammatory slant. We further consider how circulating myeloid cells enter, propagate, and persist in atherosclerotic lesions and how intimal macrophages take center stage in regulating the inflammatory milieu. In this context, we delineate emerging therapeutic strategies aimed at mitigating inflammation in atherosclerosis and how these add to existing measures toward reducing the global cardiovascular disease burden.
{"title":"Inflammation in atherosclerosis: Lessons and therapeutic implications","authors":"Peter Libby, Oliver Soehnlein","doi":"10.1016/j.immuni.2025.09.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.012","url":null,"abstract":"Inflammatory pathways operate at all stages of atherosclerosis. These processes are driven by risk factors and other stimuli that can spark inflammation by eliciting misdirected responses of intrinsic vascular cells and leukocytes, culminating in lesion initiation, progression, and complication. Continuing dissection of the key underlying inflammatory mechanisms with increasingly sophisticated tools has inspired successful clinical trials and enabled translation to the clinic. Here, we review the mechanistic understanding of the etiology and progression of atherosclerosis. We discuss how cardiovascular risk factors converge at the level of the bone marrow to perturb hematopoiesis, yielding output with a pro-inflammatory slant. We further consider how circulating myeloid cells enter, propagate, and persist in atherosclerotic lesions and how intimal macrophages take center stage in regulating the inflammatory milieu. In this context, we delineate emerging therapeutic strategies aimed at mitigating inflammation in atherosclerosis and how these add to existing measures toward reducing the global cardiovascular disease burden.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"7 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209659","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 : 2025-10-03DOI: 10.1016/j.immuni.2025.09.011
Marc Y. Donath, Daniel J. Drucker
Obesity and its related disorders, including type 2 diabetes and liver, kidney, and cardiovascular diseases, are now recognized as chronic inflammatory conditions. Here, we review the mechanisms underlying inflammation in these settings and how they may contribute to pathology. Nutrient excess triggers immune activation through pattern recognition receptors and the NLRP3 inflammasome, leading to interleukin (IL)-1β production and downstream cytokine cascades. Initially adaptive, this inflammation promotes tissue remodeling and metabolic compensation, but chronic activation contributes to insulin resistance, β cell dysfunction, and end-organ damage. We discuss the current therapeutic options, with a focus on glucagon-like peptide-1 (GLP-1) receptor agonists, which, alone or combined with additional bioactive moieties, exert notable anti-inflammatory effects. Some effects of GLP-1 medicines are independent of glucose control or weight loss, and they are attributed to direct signaling via the immune GLP-1 receptor (GLP-1R) and, indirectly, via central nervous system circuits. Understanding these mechanisms may unlock further therapeutic potential in chronic inflammatory diseases.
{"title":"Obesity, diabetes, and inflammation: Pathophysiology and clinical implications","authors":"Marc Y. Donath, Daniel J. Drucker","doi":"10.1016/j.immuni.2025.09.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.011","url":null,"abstract":"Obesity and its related disorders, including type 2 diabetes and liver, kidney, and cardiovascular diseases, are now recognized as chronic inflammatory conditions. Here, we review the mechanisms underlying inflammation in these settings and how they may contribute to pathology. Nutrient excess triggers immune activation through pattern recognition receptors and the NLRP3 inflammasome, leading to interleukin (IL)-1β production and downstream cytokine cascades. Initially adaptive, this inflammation promotes tissue remodeling and metabolic compensation, but chronic activation contributes to insulin resistance, β cell dysfunction, and end-organ damage. We discuss the current therapeutic options, with a focus on glucagon-like peptide-1 (GLP-1) receptor agonists, which, alone or combined with additional bioactive moieties, exert notable anti-inflammatory effects. Some effects of GLP-1 medicines are independent of glucose control or weight loss, and they are attributed to direct signaling via the immune GLP-1 receptor (GLP-1R) and, indirectly, via central nervous system circuits. Understanding these mechanisms may unlock further therapeutic potential in chronic inflammatory diseases.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"74 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209660","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 : 2025-10-02DOI: 10.1016/j.immuni.2025.09.008
Maegan K. Murphy, Matthew McCullen, Joshua L. Deffenbaugh, Andy Y. Chen, Joy Pai, Bence Daniel, Amir Yousif, Saravanan Raju, Sunnie Hsiung, Zhenxiao Wang, Hazem E. Ghoneim, Ansuman T. Satpathy, Marco Colonna, Eugene M. Oltz, Takeshi Egawa
During differentiation of CD8+ T cells, the transcription factors TCF-1 and Blimp1 control progenitor and terminally differentiated states, respectively. Here, we examined the hierarchy and functional consequences of cross-regulation between these factors. We identified two Blimp1-bound cis-regulatory elements, Tcf7+22kb and Tcf7+17kb, that enforced Tcf7 silencing in a context-specific manner during both acute and chronic responses. Deletion of these elements decoupled Tcf7 repression from effector differentiation but did not rewire effector T cells to a memory state or prevent the acquisition of phenotypic hallmarks of exhaustion. However, combined ablation of Prdm1 and Tcf7 preserved a memory surface phenotype despite defects in secondary expansion. Thus, the anti-proliferative and pro-differentiative effects of Blimp1 in effector or exhausted CD8+ T cells represent mechanistically distinct modules, wherein repression of Tcf7 limits proliferative capacity but not memory or progenitor specification.
{"title":"The transcriptional repressor BLIMP1 enforces TCF-1-dependent and -independent restriction of the memory fate of CD8+ T cells","authors":"Maegan K. Murphy, Matthew McCullen, Joshua L. Deffenbaugh, Andy Y. Chen, Joy Pai, Bence Daniel, Amir Yousif, Saravanan Raju, Sunnie Hsiung, Zhenxiao Wang, Hazem E. Ghoneim, Ansuman T. Satpathy, Marco Colonna, Eugene M. Oltz, Takeshi Egawa","doi":"10.1016/j.immuni.2025.09.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.008","url":null,"abstract":"During differentiation of CD8<sup>+</sup> T cells, the transcription factors TCF-1 and Blimp1 control progenitor and terminally differentiated states, respectively. Here, we examined the hierarchy and functional consequences of cross-regulation between these factors. We identified two Blimp1-bound <em>cis</em>-regulatory elements, <em>Tcf7</em><sup>+22kb</sup> and <em>Tcf7</em><sup>+17kb</sup>, that enforced <em>Tcf7</em> silencing in a context-specific manner during both acute and chronic responses. Deletion of these elements decoupled <em>Tcf7</em> repression from effector differentiation but did not rewire effector T cells to a memory state or prevent the acquisition of phenotypic hallmarks of exhaustion. However, combined ablation of <em>Prdm1</em> and <em>Tcf7</em> preserved a memory surface phenotype despite defects in secondary expansion. Thus, the anti-proliferative and pro-differentiative effects of Blimp1 in effector or exhausted CD8<sup>+</sup> T cells represent mechanistically distinct modules, wherein repression of <em>Tcf7</em> limits proliferative capacity but not memory or progenitor specification.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"19 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204019","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 : 2025-10-02DOI: 10.1016/j.immuni.2025.09.007
Mehdi Benamar, Paola Contini, Klaus Schmitz-Abe, Olga Lanzetta, Feven Getachew, Corinne Bachelin, Juan Manuel Leyva Castillo, Muyun Wang, Fatma Betul Oktelik, Océane Perrot, Yvann Batamack, Sena Nur Arbag, Emmanuel Stephen-Victor, Hani Harb, Pankaj B. Agrawal, Céline Louapre, Federico Ivaldi, Antonio Uccelli, Matilde Inglese, Claudia Angelini, Talal A. Chatila
The immune regulatory defects that promote neuroinflammation in multiple sclerosis (MS) remain unclear. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 was increased in individuals with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3+ Treg cells were induced by the gut microbiota via Toll-like receptor (TLR)-dependent mechanisms. They then translocated to the central nervous system (CNS) in EAE where they promoted disease severity. Notch3 interacted with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into T helper 17 (Th17) cells. Notch3 deletion in Treg cells prevented EAE onset by stabilizing Treg cells and by simultaneously promoting the expansion of a tissue-resident Treg cell population that expressed neuropeptide Y receptor 1 (NPY1R) and which suppressed pathogenic IFN-γ+ and GM-CSF+ T cells. Our studies thus identify altered Treg cell population dynamics as a fundamental pathogenic mechanism in autoimmune neuroinflammation.
{"title":"Notch3 destabilizes regulatory T cells to drive autoimmune neuroinflammation in multiple sclerosis","authors":"Mehdi Benamar, Paola Contini, Klaus Schmitz-Abe, Olga Lanzetta, Feven Getachew, Corinne Bachelin, Juan Manuel Leyva Castillo, Muyun Wang, Fatma Betul Oktelik, Océane Perrot, Yvann Batamack, Sena Nur Arbag, Emmanuel Stephen-Victor, Hani Harb, Pankaj B. Agrawal, Céline Louapre, Federico Ivaldi, Antonio Uccelli, Matilde Inglese, Claudia Angelini, Talal A. Chatila","doi":"10.1016/j.immuni.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.007","url":null,"abstract":"The immune regulatory defects that promote neuroinflammation in multiple sclerosis (MS) remain unclear. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 was increased in individuals with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3<sup>+</sup> Treg cells were induced by the gut microbiota via Toll-like receptor (TLR)-dependent mechanisms. They then translocated to the central nervous system (CNS) in EAE where they promoted disease severity. Notch3 interacted with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into T helper 17 (Th17) cells. <em>Notch3</em> deletion in Treg cells prevented EAE onset by stabilizing Treg cells and by simultaneously promoting the expansion of a tissue-resident Treg cell population that expressed neuropeptide Y receptor 1 (NPY1R) and which suppressed pathogenic IFN-γ<sup>+</sup> and GM-CSF<sup>+</sup> T cells. Our studies thus identify altered Treg cell population dynamics as a fundamental pathogenic mechanism in autoimmune neuroinflammation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"39 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204020","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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