Pub Date : 2025-11-14DOI: 10.1126/sciimmunol.ads8226
Danni Y. Zhu, Daniel P. Maurer, Carlos Castrillon, Yixiang Deng, Faez A. N. Mohamed, Minghe Ma, David Tang, Jessica Min-Debartolo, Nathan Higginson-Scott, Janet Buhlmann, Aaron G. Schmidt, Daniel Lingwood, Michael C. Carroll
The extrafollicular (EF) B cell differentiation pathway has emerged as a prominent source of autoantibody-secreting cells (ASCs) in systemic lupus erythematosus (SLE). CD21loCD11c+ B cells are associated with aging, infection, and autoimmunity. They are key contributors to EF ASCs, yet their developmental trajectory and receptor programming are unclear. To study EF mechanics of autoreactive B cells, we adoptively transferred naïve B cell populations into 564Igi mice, which act as an autoreactive host enriched for autoantigens and T cell help. Time-resolved analyses revealed a Toll-like receptor 7 (TLR7)–dependent early escape of peripheral tolerance and a pre–ASC division program. We identified naïve-derived CD21lo cells as precursors of EF ASCs exhibiting elevated reliance on TLR7. Repertoire analysis delineated protoautoreactive B cell selection and receptor evolution toward self-reactivity. Continuous complement receptor 2 (CR2/CD21)–complement C3d and CD21–complement iC3b engagement triggered receptor down-regulation before proliferation. We reveal CD21 as an initiator of TLR7-dependent autoimmune EF proliferation and target for suppressing autoreactivity.
{"title":"CD21 primes extrafollicular differentiation of autoreactive B cells in a TLR7-driven lupus model","authors":"Danni Y. Zhu, Daniel P. Maurer, Carlos Castrillon, Yixiang Deng, Faez A. N. Mohamed, Minghe Ma, David Tang, Jessica Min-Debartolo, Nathan Higginson-Scott, Janet Buhlmann, Aaron G. Schmidt, Daniel Lingwood, Michael C. Carroll","doi":"10.1126/sciimmunol.ads8226","DOIUrl":"10.1126/sciimmunol.ads8226","url":null,"abstract":"<div >The extrafollicular (EF) B cell differentiation pathway has emerged as a prominent source of autoantibody-secreting cells (ASCs) in systemic lupus erythematosus (SLE). CD21<sup>lo</sup>CD11c<sup>+</sup> B cells are associated with aging, infection, and autoimmunity. They are key contributors to EF ASCs, yet their developmental trajectory and receptor programming are unclear. To study EF mechanics of autoreactive B cells, we adoptively transferred naïve B cell populations into 564Igi mice, which act as an autoreactive host enriched for autoantigens and T cell help. Time-resolved analyses revealed a Toll-like receptor 7 (TLR7)–dependent early escape of peripheral tolerance and a pre–ASC division program. We identified naïve-derived CD21<sup>lo</sup> cells as precursors of EF ASCs exhibiting elevated reliance on TLR7. Repertoire analysis delineated protoautoreactive B cell selection and receptor evolution toward self-reactivity. Continuous complement receptor 2 (CR2/CD21)–complement C3d and CD21–complement iC3b engagement triggered receptor down-regulation before proliferation. We reveal CD21 as an initiator of TLR7-dependent autoimmune EF proliferation and target for suppressing autoreactivity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 113","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509425","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 : 2025-11-14DOI: 10.1126/sciimmunol.adz5181
Amélie Grosjean, Aude Jalon, Claire Leveau, Marc Diedisheim, David Alejandro Bejarano, Joyceline Cuenco, Kevin Mulder, Zhaoyuan Liu, Audrey Le Guernic, Marie-Laure Island, Jarne Walkiers, Gamze Ates, Clément Materne, Andreia Goncalves, Ivan Nemazanyy, Laura G. Baudrin, Sylvain Baulande, Martine Ropert, Jean-François Gautier, Ahmed Hamaï, Andreas Schlitzer, Florent Ginhoux, Ann Massie, Nicolas Venteclef, Elise Dalmas
Pancreatic islet-resident macrophages (IRMs) display an activated phenotype and contribute to islet development and remodeling, yet their origin, heterogeneity, and functional roles remain poorly understood. Using complementary fate-mapping systems, we show that, in adult mice, around half of IRMs originate from circulating monocytes and undergo minimal turnover. Integrated multiple single-cell RNA sequencing analyses of mouse and human islets identified four major IRM cell states that collectively reveal their inflammatory and metabolic activation. Among these, a transcriptional program driven by the cystine-glutamate antiporter SLC7A11 and enriched in CD9high IRMs was associated with enhanced antioxidant defense, mitochondrial activity, and iron-lipid metabolic pathways. We found that Slc7a11-expressing IRMs preserve β cell redox homeostasis and insulin secretion, both at baseline and under stress. These findings position IRMs as specialized immune sentinels in the endocrine pancreas and identify SLC7A11 as a key macrophage-intrinsic safeguard against oxidative stress, with broad implications for islet resilience and metabolic health.
{"title":"An islet-resident macrophage antioxidant program preserves β cell physiology","authors":"Amélie Grosjean, Aude Jalon, Claire Leveau, Marc Diedisheim, David Alejandro Bejarano, Joyceline Cuenco, Kevin Mulder, Zhaoyuan Liu, Audrey Le Guernic, Marie-Laure Island, Jarne Walkiers, Gamze Ates, Clément Materne, Andreia Goncalves, Ivan Nemazanyy, Laura G. Baudrin, Sylvain Baulande, Martine Ropert, Jean-François Gautier, Ahmed Hamaï, Andreas Schlitzer, Florent Ginhoux, Ann Massie, Nicolas Venteclef, Elise Dalmas","doi":"10.1126/sciimmunol.adz5181","DOIUrl":"10.1126/sciimmunol.adz5181","url":null,"abstract":"<div >Pancreatic islet-resident macrophages (IRMs) display an activated phenotype and contribute to islet development and remodeling, yet their origin, heterogeneity, and functional roles remain poorly understood. Using complementary fate-mapping systems, we show that, in adult mice, around half of IRMs originate from circulating monocytes and undergo minimal turnover. Integrated multiple single-cell RNA sequencing analyses of mouse and human islets identified four major IRM cell states that collectively reveal their inflammatory and metabolic activation. Among these, a transcriptional program driven by the cystine-glutamate antiporter SLC7A11 and enriched in CD9<sup>high</sup> IRMs was associated with enhanced antioxidant defense, mitochondrial activity, and iron-lipid metabolic pathways. We found that <i>Slc7a11</i>-expressing IRMs preserve β cell redox homeostasis and insulin secretion, both at baseline and under stress. These findings position IRMs as specialized immune sentinels in the endocrine pancreas and identify SLC7A11 as a key macrophage-intrinsic safeguard against oxidative stress, with broad implications for islet resilience and metabolic health.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 113","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509424","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 : 2025-11-07DOI: 10.1126/sciimmunol.aed4910
Kevin Champagne-Jorgensen, Jennifer L. Gommerman
An MS twin study links ileal Lachnospiraceae to spontaneous CNS autoimmunity in mice receiving a human microbiome transplant.
一项MS双胞胎研究将回肠毛缕菌科与接受人类微生物组移植的小鼠自发性中枢神经系统自身免疫联系起来。
{"title":"Two of a kind, one with MS: Gut microbes tip the balance","authors":"Kevin Champagne-Jorgensen, Jennifer L. Gommerman","doi":"10.1126/sciimmunol.aed4910","DOIUrl":"10.1126/sciimmunol.aed4910","url":null,"abstract":"<div >An MS twin study links ileal <i>Lachnospiraceae</i> to spontaneous CNS autoimmunity in mice receiving a human microbiome transplant.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 113","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455362","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}
Mammalian hematopoietic cells arise from mesodermal progenitors in a close developmental relationship with endothelium and along three distinct cell lineages known as primitive, prodefinitive, and definitive hematopoiesis. However, the developmental hierarchies between early mesodermal progenitors, endothelium, and blood cell lineages are incompletely understood. Here, fate-mapping, cloning, and genetic experiments identified a population of KDR+CXCR4+ prodefinitive angio-hematopoietic progenitors (PDAPs) in murine primitive streak stage mesoderm and human induced pluripotent stem cell (hiPSC) cultures. PDAPs gave rise to yolk sac (YS) and rostral (cephalic) endothelial cells and RUNX1-dependent prodefinitive hematopoietic cells, including erythro-myeloid progenitors (EMPs) and tissue macrophages, via NOTCH1-independent hemogenic endothelial cells. Notably, PDAPs did not give rise to primitive erythropoiesis or to caudal endothelium and definitive hematopoiesis. These results identify a previously unrecognized layer of lineage segregation in early mammalian mesoderm that characterizes the prodefinitive angio-hematopoietic lineage and the origin of tissue macrophages and rostral blood vessels that may be of interest for pathophysiology and cell-based therapy efforts.
{"title":"Characterization of the mammalian prodefinitive angio-hematopoietic lineage","authors":"Tomi Lazarov, Pierre-Louis Loyher, Hairu Yang, Zi-Ning Choo, Zihou Deng, Sonja Nowotschin, Ying-Yi Kuo, Ting Zhou, Araitz Alberdi-Gonzalez, Ralf Stumm, Elvira Mass, Elisa Gomez Perdiguero, Anna-Katerina Hadjantonakis, Frederic Geissmann","doi":"10.1126/sciimmunol.adt6616","DOIUrl":"10.1126/sciimmunol.adt6616","url":null,"abstract":"<div >Mammalian hematopoietic cells arise from mesodermal progenitors in a close developmental relationship with endothelium and along three distinct cell lineages known as primitive, prodefinitive, and definitive hematopoiesis. However, the developmental hierarchies between early mesodermal progenitors, endothelium, and blood cell lineages are incompletely understood. Here, fate-mapping, cloning, and genetic experiments identified a population of KDR<sup>+</sup>CXCR4<sup>+</sup> prodefinitive angio-hematopoietic progenitors (PDAPs) in murine primitive streak stage mesoderm and human induced pluripotent stem cell (hiPSC) cultures. PDAPs gave rise to yolk sac (YS) and rostral (cephalic) endothelial cells and RUNX1-dependent prodefinitive hematopoietic cells, including erythro-myeloid progenitors (EMPs) and tissue macrophages, via NOTCH1-independent hemogenic endothelial cells. Notably, PDAPs did not give rise to primitive erythropoiesis or to caudal endothelium and definitive hematopoiesis. These results identify a previously unrecognized layer of lineage segregation in early mammalian mesoderm that characterizes the prodefinitive angio-hematopoietic lineage and the origin of tissue macrophages and rostral blood vessels that may be of interest for pathophysiology and cell-based therapy efforts.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 113","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455427","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 : 2025-11-07DOI: 10.1126/sciimmunol.aed4909
Kritika Dixit, David R. Martinez
Repeated dengue infections elicit broadly neutralizing antibodies that are protective against severe disease.
反复的登革热感染引发广泛的中和抗体，对严重疾病具有保护作用。
{"title":"B cells and dengue: A cat-and-mouse game","authors":"Kritika Dixit, David R. Martinez","doi":"10.1126/sciimmunol.aed4909","DOIUrl":"10.1126/sciimmunol.aed4909","url":null,"abstract":"<div >Repeated dengue infections elicit broadly neutralizing antibodies that are protective against severe disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 113","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145456911","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 : 2025-11-07DOI: 10.1126/sciimmunol.adw0415
Xin Gao, Hayley A. McNamara, Jiwon Lee, Adrian F. Lo, Deepyan Chatterjee, Dominik Spensberger, Daniel Fernandez-Ruiz, Kevin Walz, Ke Wang, Hannah G. Kelly, Kai Pohl, Patricia E. Carreira, Andrea Do, Le Xiong, Lynette Beattie, Alexandra J. Spencer, Daniel H. D. Gray, Friedrich Frischknecht, Melanie Rug, Ian A. Cockburn
T cell–dependent antibody responses have been well studied in the context of small proteins and viruses. However, how B cells acquire and process antigens from large pathogens such as parasites remains poorly understood. Here, using Plasmodium sporozoites (SPZs) as a model, we investigated the formation of protective antibody responses against the circumsporozoite protein (CSP), a vaccine antigen expressed on the surfaces of SPZs. CSP-specific B cells took up CSP and bystander surface antigens during SPZ immunization and could obtain both intramolecular and intermolecular T cell help. Furthermore, prior exposure to blood-stage parasites—which predominantly share internal but not surface antigens with SPZs—can hinder the generation of anti-CSP antibodies. Thus, spatial relationships between the target antigens can affect CD4 T cell help to B cells. These data show how B cells obtain antigen for presentation to T cells and why malaria-exposed individuals have impaired antibody responses to CSP.
{"title":"B cells targeting parasites capture spatially linked antigens to secure T cell help","authors":"Xin Gao, Hayley A. McNamara, Jiwon Lee, Adrian F. Lo, Deepyan Chatterjee, Dominik Spensberger, Daniel Fernandez-Ruiz, Kevin Walz, Ke Wang, Hannah G. Kelly, Kai Pohl, Patricia E. Carreira, Andrea Do, Le Xiong, Lynette Beattie, Alexandra J. Spencer, Daniel H. D. Gray, Friedrich Frischknecht, Melanie Rug, Ian A. Cockburn","doi":"10.1126/sciimmunol.adw0415","DOIUrl":"10.1126/sciimmunol.adw0415","url":null,"abstract":"<div >T cell–dependent antibody responses have been well studied in the context of small proteins and viruses. However, how B cells acquire and process antigens from large pathogens such as parasites remains poorly understood. Here, using <i>Plasmodium</i> sporozoites (SPZs) as a model, we investigated the formation of protective antibody responses against the circumsporozoite protein (CSP), a vaccine antigen expressed on the surfaces of SPZs. CSP-specific B cells took up CSP and bystander surface antigens during SPZ immunization and could obtain both intramolecular and intermolecular T cell help. Furthermore, prior exposure to blood-stage parasites—which predominantly share internal but not surface antigens with SPZs—can hinder the generation of anti-CSP antibodies. Thus, spatial relationships between the target antigens can affect CD4 T cell help to B cells. These data show how B cells obtain antigen for presentation to T cells and why malaria-exposed individuals have impaired antibody responses to CSP.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 113","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adw0415","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1126/sciimmunol.adm7800
Martina Zoccheddu, Kensuke Suga, Amara Seng, Mattias N. D. Svensson, Paramita Dutta, Sanaz Panahandeh, Hadijat-Kubura Moradeke Makinde, Myungja Ro, Yizhou Wang, Hyobin Kim, Zbigniew Mikulski, Katarzyna Dobaczewska, Francesca Ingegnoli, Ruth Minsha, John F. Seagrist, Mary Carns, Kathleen Aren, Salina Dominguez, Mohammad Daud Khan, Angela Denn, Roberto Caporali, Pietro Simone Randelli, David A. McBride, Arthur M. Mandelin II, Carla Marie Cuda, Zhiping Paul Wang, Jason H. Moore, Nisarg J. Shah, Kyoung Jae Won, Deborah R. Winter, Ferhat Ay, Harris Perlman, Nunzio Bottini
T helper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We performed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferentiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4+ T cells. We demonstrate that cross-talk between TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.
类风湿关节炎（RA）患者的外周和滑膜中发现T辅助17 （ht17）细胞；然而，针对il -17的干预措施对已建立的RA的疗效有限。炎症可诱导T H 17细胞转分化为il -17阴性的exT H 17细胞，但exT H 17细胞在关节炎中的作用尚不清楚。我们在类风湿关节炎的SKG小鼠模型中进行了ht17细胞谱系追踪。在关节炎小鼠中，滑膜ht17细胞转分化为CD44 + exT h17细胞，后者更具有关节炎性，并维持不依赖IL-17的炎症。exT h17细胞基因特征包括CD44和鞘氨醇-1-磷酸受体4 （S1PR4）的上调，并与人RA滑膜CD4 + T细胞的谱相关。我们证明了th17细胞和成纤维细胞样滑膜细胞（FLSs）之间通过S1P的相互作用促进了th17 - ext h17细胞的转化。CD44对于exT h17细胞介导的关节炎是必需的。我们的研究表明，在RA进展过程中FLS的扩增促进了ht17 - ext h17细胞的转化。这些结果可能使RA精确治疗成为可能。
{"title":"TH17 cells converted into exTH17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis","authors":"Martina Zoccheddu, Kensuke Suga, Amara Seng, Mattias N. D. Svensson, Paramita Dutta, Sanaz Panahandeh, Hadijat-Kubura Moradeke Makinde, Myungja Ro, Yizhou Wang, Hyobin Kim, Zbigniew Mikulski, Katarzyna Dobaczewska, Francesca Ingegnoli, Ruth Minsha, John F. Seagrist, Mary Carns, Kathleen Aren, Salina Dominguez, Mohammad Daud Khan, Angela Denn, Roberto Caporali, Pietro Simone Randelli, David A. McBride, Arthur M. Mandelin II, Carla Marie Cuda, Zhiping Paul Wang, Jason H. Moore, Nisarg J. Shah, Kyoung Jae Won, Deborah R. Winter, Ferhat Ay, Harris Perlman, Nunzio Bottini","doi":"10.1126/sciimmunol.adm7800","DOIUrl":"10.1126/sciimmunol.adm7800","url":null,"abstract":"<div >T helper 17 (T<sub>H</sub>17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce T<sub>H</sub>17 cell transdifferentiation into IL-17–negative exT<sub>H</sub>17 cells, but the role of exT<sub>H</sub>17 cells in arthritis is unknown. We performed T<sub>H</sub>17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial T<sub>H</sub>17 cells transdifferentiate into CD44<sup>+</sup> exT<sub>H</sub>17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exT<sub>H</sub>17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4<sup>+</sup> T cells. We demonstrate that cross-talk between T<sub>H</sub>17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes T<sub>H</sub>17-exT<sub>H</sub>17 cell conversion. CD44 is necessary for exT<sub>H</sub>17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes T<sub>H</sub>17-exT<sub>H</sub>17 cell conversion. These results could potentially enable RA precision therapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 113","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455363","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 : 2025-10-31DOI: 10.1126/sciimmunol.adw1992
Kevin Man, Vinicius A. Duarte da Silva, Nikita Potemkin, Sarah S. Gabriel, Teisha Mason, Tarek Elmzzahi, Marcela De Lima Moreira, Chun-Hsi Su, Laura Mackay, Marc D. Beyer, Jan Schröder, Georg Gasteiger, Axel Kallies
Tissue-resident memory T (TRM) cells provide localized immunity against intracellular pathogens and cancer. Upon antigen reencounter, TRM cells differentiate into effector cells while also giving rise to another generation of memory cells. Here, we show that intestinal TRM cells that express the transcriptional regulators TCF1 or ID3 exhibit stem-like memory properties and are endowed with a superior capacity to regenerate effector and memory T cells after pathogen reencounter. Ablation of TCF1 using a TRM cell–specific mouse model resulted in impaired formation of intestinal TRM cells, altered their transcriptional heterogeneity, and increased their differentiation into tissue-confined and recirculating CX3CR1+ effector cells during recall. TGF-β and retinoic acid were required for formation and survival of TCF1- and ID3-expressing TRM cells and restrained their differentiation into CX3CR1+ effector cells during reinfection. Thus, stem-like cells control the quality and recall capacity of TRM cells, thereby contributing to anamnestic memory responses.
{"title":"Stem-like tissue-resident memory T cells control functional heterogeneity and reactivation of T cell memory in the intestine","authors":"Kevin Man, Vinicius A. Duarte da Silva, Nikita Potemkin, Sarah S. Gabriel, Teisha Mason, Tarek Elmzzahi, Marcela De Lima Moreira, Chun-Hsi Su, Laura Mackay, Marc D. Beyer, Jan Schröder, Georg Gasteiger, Axel Kallies","doi":"10.1126/sciimmunol.adw1992","DOIUrl":"10.1126/sciimmunol.adw1992","url":null,"abstract":"<div >Tissue-resident memory T (T<sub>RM</sub>) cells provide localized immunity against intracellular pathogens and cancer. Upon antigen reencounter, T<sub>RM</sub> cells differentiate into effector cells while also giving rise to another generation of memory cells. Here, we show that intestinal T<sub>RM</sub> cells that express the transcriptional regulators TCF1 or ID3 exhibit stem-like memory properties and are endowed with a superior capacity to regenerate effector and memory T cells after pathogen reencounter. Ablation of TCF1 using a T<sub>RM</sub> cell–specific mouse model resulted in impaired formation of intestinal T<sub>RM</sub> cells, altered their transcriptional heterogeneity, and increased their differentiation into tissue-confined and recirculating CX3CR1<sup>+</sup> effector cells during recall. TGF-β and retinoic acid were required for formation and survival of TCF1- and ID3-expressing T<sub>RM</sub> cells and restrained their differentiation into CX3CR1<sup>+</sup> effector cells during reinfection. Thus, stem-like cells control the quality and recall capacity of T<sub>RM</sub> cells, thereby contributing to anamnestic memory responses.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405217","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 : 2025-10-31DOI: 10.1126/sciimmunol.adu3718
Fiamma Salerno, Alex J. Whale, Louise S. Matheson, Davide Vespasiani, William S. Foster, Twm J. Mitchell, Michael Screen, Melanie Stammers, Sarah E. Bell, Daniel J. Hodson, Hamish W. King, Michelle A. Linterman, Jonathan Houseley, Martin Turner
The germinal center (GC) reaction drives the production of high-affinity antibodies by iterative cycles of B cell somatic hypermutation, selection, and proliferation. How GC B cells undergo rapid cell division while maintaining genome stability is poorly understood. Here, we show that the RNA binding proteins ZFP36L1 and ZFP36L2 act downstream of antigen sensing and protect GC B cells from replication stress by controlling a cell cycle–related posttranscriptional regulon. They safeguard the successful completion of mitosis by balancing CDK1 and p21-mediated regulation of cell-cycle progression. In their absence, GC B cells are prone to arrest in the G2-M phase and die by apoptosis, resulting in curtailed GC responses. DNA replication forks stalled at active replication initiation zones, causing replication stress and increased activity of the ATR-CHK1 DNA damage response. Thus, RNA binding proteins guide posttranscriptional gene regulation and maintain a functional G2-M checkpoint in GC B cells.
{"title":"RNA binding proteins control the G2-M checkpoint of the germinal center B cell","authors":"Fiamma Salerno, Alex J. Whale, Louise S. Matheson, Davide Vespasiani, William S. Foster, Twm J. Mitchell, Michael Screen, Melanie Stammers, Sarah E. Bell, Daniel J. Hodson, Hamish W. King, Michelle A. Linterman, Jonathan Houseley, Martin Turner","doi":"10.1126/sciimmunol.adu3718","DOIUrl":"10.1126/sciimmunol.adu3718","url":null,"abstract":"<div >The germinal center (GC) reaction drives the production of high-affinity antibodies by iterative cycles of B cell somatic hypermutation, selection, and proliferation. How GC B cells undergo rapid cell division while maintaining genome stability is poorly understood. Here, we show that the RNA binding proteins ZFP36L1 and ZFP36L2 act downstream of antigen sensing and protect GC B cells from replication stress by controlling a cell cycle–related posttranscriptional regulon. They safeguard the successful completion of mitosis by balancing CDK1 and p21-mediated regulation of cell-cycle progression. In their absence, GC B cells are prone to arrest in the G<sub>2</sub>-M phase and die by apoptosis, resulting in curtailed GC responses. DNA replication forks stalled at active replication initiation zones, causing replication stress and increased activity of the ATR-CHK1 DNA damage response. Thus, RNA binding proteins guide posttranscriptional gene regulation and maintain a functional G<sub>2</sub>-M checkpoint in GC B cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405215","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 : 2025-10-31DOI: 10.1126/sciimmunol.adx1135
Saya Satoh, Yaw Bia Tan, Benjamin Heil, Shintaro Yamada, Verena Schütte, Celest Phang, Chaozhi Tang, Yuta Tsukamoto, Takahiro Higuchi, Takashi Fujita, Rayk Behrendt, Martin Schlee, Dahai Luo, Hiroki Kato
Detecting viral RNA by the ubiquitously expressed cytosolic receptor retinoic acid–inducible gene I (RIG-I) is critical for antiviral immune responses, including type I interferon (IFN-I) and chemokine induction. RIG-I has evolved to sensitively recognize viral RNA but tolerate self-RNA. RIG-I mutations causing self-tolerance loss induce IFN-I and chemokines in patients, initiating autoinflammation. We observed that mice expressing the RIG-I patient variant E373A spontaneously developed lupus-like nephritis. Kidney-derived chemokines attracted monocytes through CCR2 (C-C motif chemokine receptor 2) and induced interstitial inflammation and tubular damage. This led to renal dysfunction independently of immunoglobulin G–nucleic acid complex deposition. Sequencing of RIG-I E373A–bound RNA from kidney-derived cells identified short noncoding Y-RNA. Deletion of the most enriched Y-RNA species reduced RIG-I E373A–induced IFN-I responses. Cryo–electron microscopy and molecular analyses revealed that RIG-I E373A binding to the Y-RNA stem region resulted in its activation. Thus, we demonstrate that Y-RNA activates a RIG-I gain-of-function mutant in a tissue-specific manner, causing autoinflammation culminating in lupus nephritis.
{"title":"Local activation of mutant RIG-I by short noncoding Y-RNA in the kidney triggers lethal nephritis","authors":"Saya Satoh, Yaw Bia Tan, Benjamin Heil, Shintaro Yamada, Verena Schütte, Celest Phang, Chaozhi Tang, Yuta Tsukamoto, Takahiro Higuchi, Takashi Fujita, Rayk Behrendt, Martin Schlee, Dahai Luo, Hiroki Kato","doi":"10.1126/sciimmunol.adx1135","DOIUrl":"10.1126/sciimmunol.adx1135","url":null,"abstract":"<div >Detecting viral RNA by the ubiquitously expressed cytosolic receptor retinoic acid–inducible gene I (RIG-I) is critical for antiviral immune responses, including type I interferon (IFN-I) and chemokine induction. RIG-I has evolved to sensitively recognize viral RNA but tolerate self-RNA. RIG-I mutations causing self-tolerance loss induce IFN-I and chemokines in patients, initiating autoinflammation. We observed that mice expressing the RIG-I patient variant E373A spontaneously developed lupus-like nephritis. Kidney-derived chemokines attracted monocytes through CCR2 (C-C motif chemokine receptor 2) and induced interstitial inflammation and tubular damage. This led to renal dysfunction independently of immunoglobulin G–nucleic acid complex deposition. Sequencing of RIG-I E373A–bound RNA from kidney-derived cells identified short noncoding Y-RNA. Deletion of the most enriched Y-RNA species reduced RIG-I E373A–induced IFN-I responses. Cryo–electron microscopy and molecular analyses revealed that RIG-I E373A binding to the Y-RNA stem region resulted in its activation. Thus, we demonstrate that Y-RNA activates a RIG-I gain-of-function mutant in a tissue-specific manner, causing autoinflammation culminating in lupus nephritis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 112","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405216","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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