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}
Pub Date : 2025-10-02DOI: 10.1016/j.immuni.2025.09.004
Ping Zhang, Françoise Haeseleer, Olivia G. Waltner, Kate H. Gartlan, Shruti S. Bhise, Simone A. Minnie, Rachael C. Adams, Albert C. Yeh, Kathleen S. Ensbey, Samuel R.W. Legg, Tomoko Sekiguchi, Erden Atilla, Nicole S. Nemychenkov, Ethan L. Nelson, Tanvi Joshi, Emily C. Liang, Alexandre V. Hirayama, Kokoro Abe, Motoko Koyama, Andrew D. Clouston, Geoffrey R. Hill
Interleukin 10 (IL-10)-producing CD4+ type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation. However, specific Eomesodermin (Eomes)-dependent stages of Tr1 differentiation and function remain unclear. Using preclinical models of bone marrow transplantation (BMT), we demonstrated a Tr1 differentiation trajectory in vivo from Eomes+IL-10− to Eomes+IL-10+ subsets with the acquisition of cytokine, cytolytic, and exhaustion features. The Eomes+CD4+ fraction represented the dominant cytotoxic subset after BMT, mediating graft-versus-leukemia effects while limiting inflammation. In CD19-targeted chimeric antigen receptor (CAR) T cell immunotherapy, Eomes drove the same CD4+ Tr1 phenotype that controlled cytolysis, while mitigating immune toxicity and promoting persistence. In individuals with high-grade B cell lymphomas that had long-term disease control after receiving commercial CD19-targeted CAR T cells, Eomes+ Tr1 cells represented a stable population comprising 40%–80% of the CD4+ CAR T cell population. Hence, Eomes controls both regulatory and cytotoxic programs in CD4+ T cells, essential for curative immunotherapy outcomes.
{"title":"Eomesodermin+ CD4+ T cells are critical for curative immunotherapy outcomes","authors":"Ping Zhang, Françoise Haeseleer, Olivia G. Waltner, Kate H. Gartlan, Shruti S. Bhise, Simone A. Minnie, Rachael C. Adams, Albert C. Yeh, Kathleen S. Ensbey, Samuel R.W. Legg, Tomoko Sekiguchi, Erden Atilla, Nicole S. Nemychenkov, Ethan L. Nelson, Tanvi Joshi, Emily C. Liang, Alexandre V. Hirayama, Kokoro Abe, Motoko Koyama, Andrew D. Clouston, Geoffrey R. Hill","doi":"10.1016/j.immuni.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.004","url":null,"abstract":"Interleukin 10 (IL-10)-producing CD4<sup>+</sup> type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation. However, specific Eomesodermin (Eomes)-dependent stages of Tr1 differentiation and function remain unclear. Using preclinical models of bone marrow transplantation (BMT), we demonstrated a Tr1 differentiation trajectory <em>in vivo</em> from Eomes<sup>+</sup>IL-10<sup>−</sup> to Eomes<sup>+</sup>IL-10<sup>+</sup> subsets with the acquisition of cytokine, cytolytic, and exhaustion features. The Eomes<sup>+</sup>CD4<sup>+</sup> fraction represented the dominant cytotoxic subset after BMT, mediating graft-versus-leukemia effects while limiting inflammation. In CD19-targeted chimeric antigen receptor (CAR) T cell immunotherapy, Eomes drove the same CD4<sup>+</sup> Tr1 phenotype that controlled cytolysis, while mitigating immune toxicity and promoting persistence. In individuals with high-grade B cell lymphomas that had long-term disease control after receiving commercial CD19-targeted CAR T cells, Eomes<sup>+</sup> Tr1 cells represented a stable population comprising 40%–80% of the CD4<sup>+</sup> CAR T cell population. Hence, Eomes controls both regulatory and cytotoxic programs in CD4<sup>+</sup> T cells, essential for curative immunotherapy outcomes.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"49 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204021","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 : 2025-09-25DOI: 10.1016/j.immuni.2025.09.001
Mrinmoy Das, Mohammed Alasharee, Brian Woods, Saikat Mukherjee, Shira Kim, Megan Elkins, Jacqueline Ngo, Logan Magin, Maheshwor Timilshina, Juan Manuel Leyva-Castillo, Kenneth M. Murphy, Robert M. Anthony, Ana Flávia Santarine Laureano, George F. Murphy, Shannon McNamee, Frank Brombacher, Simon P. Hogan, Jerrold R. Turner, Shabnam Abtahi, Wanda Phipatanakul, Raif S. Geha
The mechanism of the association of S. aureus skin colonization with food allergy in atopic dermatitis (AD) is unknown. Interleukin-4 (IL-4) plays an important role in food allergy. We found elevated serum IL-4 concentrations in AD patients with S. aureus skin colonization and food allergy. Using an AD mouse model, we demonstrated that epicutaneous application of antigen together with superantigen-producing S. aureus, or staphylococcal enterotoxin B (SEB), caused a heightened systemic antigen-specific T helper-2 (Th2) response and elevated serum IL-4 concentrations. T cell-derived IL-4 acted on intestinal epithelial cells to enhance intestinal permeability and anaphylaxis to enteral antigen challenge. CD40-dependent SEB binding to keratinocytes triggered IL-33 release, which caused T cells to produce IL-3 that elicited a basophil influx in skin-draining lymph nodes (dLNs). Basophil-derived IL-4 augmented Th2 cell polarization by antigen-bearing dendritic cells from skin dLNs. These results suggest therapeutic interventions that might attenuate food allergy in AD patients.
{"title":"S. aureus exposure during cutaneous antigen sensitization causes basophil- and interleukin-4-dependent exaggerated food anaphylaxis","authors":"Mrinmoy Das, Mohammed Alasharee, Brian Woods, Saikat Mukherjee, Shira Kim, Megan Elkins, Jacqueline Ngo, Logan Magin, Maheshwor Timilshina, Juan Manuel Leyva-Castillo, Kenneth M. Murphy, Robert M. Anthony, Ana Flávia Santarine Laureano, George F. Murphy, Shannon McNamee, Frank Brombacher, Simon P. Hogan, Jerrold R. Turner, Shabnam Abtahi, Wanda Phipatanakul, Raif S. Geha","doi":"10.1016/j.immuni.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.001","url":null,"abstract":"The mechanism of the association of <em>S. aureus</em> skin colonization with food allergy in atopic dermatitis (AD) is unknown. Interleukin-4 (IL-4) plays an important role in food allergy. We found elevated serum IL-4 concentrations in AD patients with <em>S. aureus</em> skin colonization and food allergy. Using an AD mouse model, we demonstrated that epicutaneous application of antigen together with superantigen-producing <em>S. aureus</em>, or staphylococcal enterotoxin B (SEB), caused a heightened systemic antigen-specific T helper-2 (Th2) response and elevated serum IL-4 concentrations. T cell-derived IL-4 acted on intestinal epithelial cells to enhance intestinal permeability and anaphylaxis to enteral antigen challenge. CD40-dependent SEB binding to keratinocytes triggered IL-33 release, which caused T cells to produce IL-3 that elicited a basophil influx in skin-draining lymph nodes (dLNs). Basophil-derived IL-4 augmented Th2 cell polarization by antigen-bearing dendritic cells from skin dLNs. These results suggest therapeutic interventions that might attenuate food allergy in AD patients.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"4 3 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141183","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 : 2025-09-25DOI: 10.1016/j.immuni.2025.09.002
Sara Polletti, Júlia Melià-Alomà, Francesco Pileri, Chiara Anna Di Lena, Viviana Piccolo, Alessandro Cuomo, Tomas Stopka, Francesco Gualdrini, Gioacchino Natoli
The interplay between chromatin remodelers and pioneer transcription factors (TFs) regulates cis-regulatory element accessibility to maintain cell identity and transcriptional fidelity. We investigated the impact of imitation of switch (ISWI) chromatin remodelers, key regulators of nucleosome spacing, on macrophage differentiation and activation, focusing on SMARCA5, the sole ISWI ATPase in myeloid cells. Conditional Smarca5 deletion in bone marrow-derived macrophages disrupted nucleosome phasing near sites bound by PU.1, a pioneer TF essential for myeloid identity, without altering PU.1 occupancy. However, SMARCA5 loss increased accessibility at motifs bound by C/EBPβ, a weak pioneer TF, enabling binding to regulatory regions active in non-hematopoietic lineages and causing lineage-inappropriate transcription. These changes also increased accessibility at sites bound by stimulus-induced TFs, leading to macrophage hyperactivation and mis-expression of stimulus-inappropriate genes. Thus, SMARCA5-dependent nucleosome phasing restrains C/EBPβ and stimulus-induced TF binding, ensuring transcriptional fidelity during macrophage lineage specification and activation, with likely similar roles in other immune cell types.
{"title":"Control of myeloid lineage fidelity and response to stimuli by ISWI-enforced nucleosome phasing","authors":"Sara Polletti, Júlia Melià-Alomà, Francesco Pileri, Chiara Anna Di Lena, Viviana Piccolo, Alessandro Cuomo, Tomas Stopka, Francesco Gualdrini, Gioacchino Natoli","doi":"10.1016/j.immuni.2025.09.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.09.002","url":null,"abstract":"The interplay between chromatin remodelers and pioneer transcription factors (TFs) regulates <em>cis</em>-regulatory element accessibility to maintain cell identity and transcriptional fidelity. We investigated the impact of imitation of switch (ISWI) chromatin remodelers, key regulators of nucleosome spacing, on macrophage differentiation and activation, focusing on SMARCA5, the sole ISWI ATPase in myeloid cells. Conditional <em>Smarca5</em> deletion in bone marrow-derived macrophages disrupted nucleosome phasing near sites bound by PU.1, a pioneer TF essential for myeloid identity, without altering PU.1 occupancy. However, SMARCA5 loss increased accessibility at motifs bound by C/EBPβ, a weak pioneer TF, enabling binding to regulatory regions active in non-hematopoietic lineages and causing lineage-inappropriate transcription. These changes also increased accessibility at sites bound by stimulus-induced TFs, leading to macrophage hyperactivation and mis-expression of stimulus-inappropriate genes. Thus, SMARCA5-dependent nucleosome phasing restrains C/EBPβ and stimulus-induced TF binding, ensuring transcriptional fidelity during macrophage lineage specification and activation, with likely similar roles in other immune cell types.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"63 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141001","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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