Pub Date : 2026-02-06DOI: 10.1126/sciimmunol.adx8474
Lena S. Mayer, Jakob Arnold, Felix Roettele, Nadine Reuter, Ajinkya Pattekar, Takuya Ohtani, Mariana M. Ribeiro, Rebecca Siwicki, Kerstin Bruder, David Obwegs, Elin Stahl, Sarah Buechel, Natascha Roehlen, Julia Kolter, Zohreh Mansoori Moghadam, Ahmed Alaswad, Zhibek Zhumalidova, Guang Li, Xinjuan Liu, Yang Li, Amit Singh, Jose Villacorta Hidalgo, Maria D. Paraskevopoulou, Vijay Yajnik, Julius Juarez, Yue Ren, Hongzhe Li, E. John Wherry, James D. Lewis, Gary D. Wu, Meenakshi Bewtra, Vesselin T. Tomov, Robert Thimme, Bertram Bengsch, Peter Hasselblatt, Simone Picelli, Maike Hofmann, Sagar
γδ T cells maintain intestinal immune homeostasis, but their contributions to human ulcerative colitis (UC) are poorly understood. We characterized γδ T cells in intestinal biopsies obtained from patients with UC and healthy donors using single-cell RNA sequencing, T cell receptor profiling, and mass cytometry. UC reduced CD103+Vγ4Vδ1+ γδ intraepithelial lymphocytes (γδ IELs) and increased γδ T cell subsets with stemlike phenotypes expressing TCF-1 (T cell factor 1) and PD-1 (programmed cell death receptor 1) or effector-like phenotypes expressing granzyme B, perforin, and T-bet in the lamina propria. γδ T cell composition changes in UC correlated with decreased expression of epithelial BTNL3 and BTNL8 and increased BTN3A1 and BTN3A3, suggesting altered recruitment and activation. Clinical improvement recovered γδ IELs and reduced inflammation-associated subsets. Inflammation-associated changes were observed in peripheral blood γδ T cells. Thus, distinct γδ T cell subsets in different niches exert protective or pathogenic functions in UC.
{"title":"Single-cell profiling reveals diverse γδ T cell subsets in ulcerative colitis","authors":"Lena S. Mayer, Jakob Arnold, Felix Roettele, Nadine Reuter, Ajinkya Pattekar, Takuya Ohtani, Mariana M. Ribeiro, Rebecca Siwicki, Kerstin Bruder, David Obwegs, Elin Stahl, Sarah Buechel, Natascha Roehlen, Julia Kolter, Zohreh Mansoori Moghadam, Ahmed Alaswad, Zhibek Zhumalidova, Guang Li, Xinjuan Liu, Yang Li, Amit Singh, Jose Villacorta Hidalgo, Maria D. Paraskevopoulou, Vijay Yajnik, Julius Juarez, Yue Ren, Hongzhe Li, E. John Wherry, James D. Lewis, Gary D. Wu, Meenakshi Bewtra, Vesselin T. Tomov, Robert Thimme, Bertram Bengsch, Peter Hasselblatt, Simone Picelli, Maike Hofmann, Sagar","doi":"10.1126/sciimmunol.adx8474","DOIUrl":"10.1126/sciimmunol.adx8474","url":null,"abstract":"<div >γδ T cells maintain intestinal immune homeostasis, but their contributions to human ulcerative colitis (UC) are poorly understood. We characterized γδ T cells in intestinal biopsies obtained from patients with UC and healthy donors using single-cell RNA sequencing, T cell receptor profiling, and mass cytometry. UC reduced CD103<sup>+</sup>Vγ4Vδ1<sup>+</sup> γδ intraepithelial lymphocytes (γδ IELs) and increased γδ T cell subsets with stemlike phenotypes expressing TCF-1 (T cell factor 1) and PD-1 (programmed cell death receptor 1) or effector-like phenotypes expressing granzyme B, perforin, and T-bet in the lamina propria. γδ T cell composition changes in UC correlated with decreased expression of epithelial <i>BTNL3</i> and <i>BTNL8</i> and increased <i>BTN3A1</i> and <i>BTN3A3</i>, suggesting altered recruitment and activation. Clinical improvement recovered γδ IELs and reduced inflammation-associated subsets. Inflammation-associated changes were observed in peripheral blood γδ T cells. Thus, distinct γδ T cell subsets in different niches exert protective or pathogenic functions in UC.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 116","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122867","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 : 2026-02-06DOI: 10.1126/sciimmunol.aef9196
Cait A. McAlindon, Rachael A. Clark
Aldehydes accumulating in response to reduced fatty acid oxidation in tumor-infiltrating lymphocytes damage mitochondria and drive T cell exhaustion.
在肿瘤浸润淋巴细胞中，由于脂肪酸氧化减少，醛的积累会损害线粒体，并导致T细胞衰竭。
{"title":"Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells","authors":"Cait A. McAlindon, Rachael A. Clark","doi":"10.1126/sciimmunol.aef9196","DOIUrl":"10.1126/sciimmunol.aef9196","url":null,"abstract":"<div >Aldehydes accumulating in response to reduced fatty acid oxidation in tumor-infiltrating lymphocytes damage mitochondria and drive T cell exhaustion.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 116","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122865","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 : 2026-02-06DOI: 10.1126/sciimmunol.adx4622
Nicholas M. Adams, Aleksandra Galitsyna, Ioanna Tiniakou, Eduardo Esteva, Ai C. Ra, Daniel Martinez-Krams, Colleen M. Lau, Jojo Reyes, Nezar Abdennur, Alexey Shkolikov, George S. Yap, Alireza Khodadadi-Jamayran, Igor Dolgalev, Leonid A. Mirny, Boris Reizis
The cohesin complex extrudes chromatin loops, stopping at sites bound by CCCTC-binding factor (CTCF) and organizing chromosomes into topologically associated domains, yet biological implications of this process remain obscure. We show that cohesin controls the in vivo differentiation and function of murine antigen-presenting dendritic cells (DCs), particularly antigen cross-presentation and interleukin-12 (IL-12) secretion by type 1 conventional DCs (cDC1s). The chromatin organization of DCs was shaped by cohesin and the transcription factor IRF8, which facilitated chromatin looping and chromosome compartmentalization, respectively. Optimal expression of IRF8 itself required CTCF/cohesin binding sites demarcating the Irf8 gene. During DC activation, cohesin enabled the induction of a subset of genes that were preferentially located in Polycomb-repressed regions and enriched in more distal enhancers. Accordingly, deletion of CTCF sites flanking the Il12b gene in mice reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin folding in cell differentiation and function in vivo and its bidirectional cross-talk with lineage-specifying transcription factors.
{"title":"Cohesin-mediated chromatin organization controls the differentiation and function of dendritic cells","authors":"Nicholas M. Adams, Aleksandra Galitsyna, Ioanna Tiniakou, Eduardo Esteva, Ai C. Ra, Daniel Martinez-Krams, Colleen M. Lau, Jojo Reyes, Nezar Abdennur, Alexey Shkolikov, George S. Yap, Alireza Khodadadi-Jamayran, Igor Dolgalev, Leonid A. Mirny, Boris Reizis","doi":"10.1126/sciimmunol.adx4622","DOIUrl":"10.1126/sciimmunol.adx4622","url":null,"abstract":"<div >The cohesin complex extrudes chromatin loops, stopping at sites bound by CCCTC-binding factor (CTCF) and organizing chromosomes into topologically associated domains, yet biological implications of this process remain obscure. We show that cohesin controls the in vivo differentiation and function of murine antigen-presenting dendritic cells (DCs), particularly antigen cross-presentation and interleukin-12 (IL-12) secretion by type 1 conventional DCs (cDC1s). The chromatin organization of DCs was shaped by cohesin and the transcription factor IRF8, which facilitated chromatin looping and chromosome compartmentalization, respectively. Optimal expression of IRF8 itself required CTCF/cohesin binding sites demarcating the <i>Irf8</i> gene. During DC activation, cohesin enabled the induction of a subset of genes that were preferentially located in Polycomb-repressed regions and enriched in more distal enhancers. Accordingly, deletion of CTCF sites flanking the <i>Il12b</i> gene in mice reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin folding in cell differentiation and function in vivo and its bidirectional cross-talk with lineage-specifying transcription factors.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 116","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122866","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}
{"title":"The dark side of the dot: How melanosomes dim T cell activity","authors":"Ruimin Wang, Etienne Caron","doi":"10.1126/sciimmunol.aef9200","DOIUrl":"10.1126/sciimmunol.aef9200","url":null,"abstract":"<div >Melanoma cells evade immune detection by secreting MHC-peptide–loaded melanosomes that interact with and impair CD8+ TCRs.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 116","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122869","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 : 2026-02-06DOI: 10.1126/sciimmunol.adr6376
James E. Parkinson, Judith E. Allen, Lucy H. Jackson-Jones
The serous cavities are fluid-filled spaces that surround the lung, heart, and abdomen. One of their main functions is to provide protection and lubrication for their encapsulated organs. In addition to these physiological roles, the serous cavities are rich immune cell reservoirs. Although these cavity-derived immune cells have been studied ex vivo for many years, the past decade has led to substantial advances in serous cavity biology. Importantly, immune mechanisms that occur in these fluid environments and communication networks between these cavities and the tissues that they contain have been elucidated. In this Review, we aim to summarize the current knowledge of cellular and molecular interactions that govern immunology across all serous cavities, comparing animal models and human studies. A deeper understanding of how the serous cavities provide immune protection to the tissues that they encompass is likely to reveal therapeutic avenues for manipulation of these cavities to improve disease outcomes.
{"title":"Immunobiology of the serous cavities","authors":"James E. Parkinson, Judith E. Allen, Lucy H. Jackson-Jones","doi":"10.1126/sciimmunol.adr6376","DOIUrl":"10.1126/sciimmunol.adr6376","url":null,"abstract":"<div >The serous cavities are fluid-filled spaces that surround the lung, heart, and abdomen. One of their main functions is to provide protection and lubrication for their encapsulated organs. In addition to these physiological roles, the serous cavities are rich immune cell reservoirs. Although these cavity-derived immune cells have been studied ex vivo for many years, the past decade has led to substantial advances in serous cavity biology. Importantly, immune mechanisms that occur in these fluid environments and communication networks between these cavities and the tissues that they contain have been elucidated. In this Review, we aim to summarize the current knowledge of cellular and molecular interactions that govern immunology across all serous cavities, comparing animal models and human studies. A deeper understanding of how the serous cavities provide immune protection to the tissues that they encompass is likely to reveal therapeutic avenues for manipulation of these cavities to improve disease outcomes.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 116","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122868","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 : 2026-01-30DOI: 10.1126/sciimmunol.ady7328
Karel F. A. Van Damme, Dorine Sichien, Katrien Van der Borght, Justine Van Moorleghem, Sofie Van Gassen, Joseph Jorssen, Seppe De Winter, Elisabeth De Leeuw, Caihong Wang, Qingqing Chai, Anna Brotcke Zumsteg, Michael A. Schmid, Victor Bosteels, Pieter De Bleser, Manon Vanheerswynghels, Sofie De Prijck, Anna Bujko, Clint De Nolf, Martijn J. Schuijs, Bram Van Den Eeckhout, Ilse Rogiers, Robin Browaeys, Flore Thielemans, Katrien Quintelier, Jinke D’Hont, Tino Hochepied, Patricia Isnard Petit, Séverine Augier, Rachel Courtois, Stijn Verwaerde, Stijn Vanhee, Sjoerd Schetters, Charlotte L. Scott, Stein Aerts, Yvan Saeys, Alan J. Korman, Fabio Benigni, Davide Corti, Sophie Janssens, Niels Vandamme, Antonio P. Baptista, Christophe Desmet, Dirk Elewaut, Hamida Hammad, Ariane Morel, Eric Vivier, Fabiane Sônego, Kader Thiam, Sofie Voet, Bianca Balbino, Bart N. Lambrecht
Fc receptors mediate antibody effector functions. Immunoglobulin G (IgG), the predominant antibody in circulation and in clinical use, engages diverse Fc gamma (Fcγ) receptors differentially expressed across cell types. Here, we provide a comprehensive overview of Fcγ receptor and neonatal Fc receptor (FcRn) expression in humans, macaques, and mice. This analysis revealed substantial differences in Fcγ receptor diversity, cell-specific expression, and regulatory mechanisms that compromise the translation of mouse and macaque models for antibody research. To improve preclinical modeling, we generated a mouse in which humanized Fcγ receptors (FcγRI/CD64, FcγRIIA/CD32A, FcγRIIB/CD32B, FcγRIIIA/CD16A, and FcγRIIIB/CD16B), expressed under control of human promotors, replace their murine counterparts. This model also incorporates human FcRn to improve antibody pharmacokinetics. Humanization resulted in more faithful Fcγ receptor expression. We validated receptor functionality and demonstrated how cytokines modulate their expression. Together, this cross-species Fcγ receptor atlas and humanized mouse model can improve the preclinical evaluation of antibody-based therapeutics.
Fc受体介导抗体效应功能。免疫球蛋白G （IgG）是循环和临床使用的主要抗体，参与不同细胞类型差异表达的多种Fcγ (Fcγ)受体。在这里，我们提供了Fcγ受体和新生Fc受体（FcRn）在人类、猕猴和小鼠中的表达的全面概述。该分析揭示了Fcγ受体多样性、细胞特异性表达和调节机制的实质性差异，这些差异影响了小鼠和猕猴模型在抗体研究中的翻译。为了改善临床前建模，我们在小鼠中建立了人源化的Fcγ受体（Fcγ ri /CD64、Fcγ riia /CD32A、Fcγ riib /CD32B、Fcγ riiia /CD16A和Fcγ riiib /CD16B），这些受体在人启动子的控制下表达，取代了小鼠的相应受体。该模型还加入了人FcRn以改善抗体药代动力学。人源化导致更忠实的Fcγ受体表达。我们验证了受体的功能，并展示了细胞因子如何调节它们的表达。总之，这种跨物种Fcγ受体图谱和人源化小鼠模型可以改善基于抗体的治疗方法的临床前评估。
{"title":"Cross-species cellular mapping and humanization of Fcγ receptors to advance antibody modeling","authors":"Karel F. A. Van Damme, Dorine Sichien, Katrien Van der Borght, Justine Van Moorleghem, Sofie Van Gassen, Joseph Jorssen, Seppe De Winter, Elisabeth De Leeuw, Caihong Wang, Qingqing Chai, Anna Brotcke Zumsteg, Michael A. Schmid, Victor Bosteels, Pieter De Bleser, Manon Vanheerswynghels, Sofie De Prijck, Anna Bujko, Clint De Nolf, Martijn J. Schuijs, Bram Van Den Eeckhout, Ilse Rogiers, Robin Browaeys, Flore Thielemans, Katrien Quintelier, Jinke D’Hont, Tino Hochepied, Patricia Isnard Petit, Séverine Augier, Rachel Courtois, Stijn Verwaerde, Stijn Vanhee, Sjoerd Schetters, Charlotte L. Scott, Stein Aerts, Yvan Saeys, Alan J. Korman, Fabio Benigni, Davide Corti, Sophie Janssens, Niels Vandamme, Antonio P. Baptista, Christophe Desmet, Dirk Elewaut, Hamida Hammad, Ariane Morel, Eric Vivier, Fabiane Sônego, Kader Thiam, Sofie Voet, Bianca Balbino, Bart N. Lambrecht","doi":"10.1126/sciimmunol.ady7328","DOIUrl":"10.1126/sciimmunol.ady7328","url":null,"abstract":"<div >Fc receptors mediate antibody effector functions. Immunoglobulin G (IgG), the predominant antibody in circulation and in clinical use, engages diverse Fc gamma (Fcγ) receptors differentially expressed across cell types. Here, we provide a comprehensive overview of Fcγ receptor and neonatal Fc receptor (FcRn) expression in humans, macaques, and mice. This analysis revealed substantial differences in Fcγ receptor diversity, cell-specific expression, and regulatory mechanisms that compromise the translation of mouse and macaque models for antibody research. To improve preclinical modeling, we generated a mouse in which humanized Fcγ receptors (FcγRI/CD64, FcγRIIA/CD32A, FcγRIIB/CD32B, FcγRIIIA/CD16A, and FcγRIIIB/CD16B), expressed under control of human promotors, replace their murine counterparts. This model also incorporates human FcRn to improve antibody pharmacokinetics. Humanization resulted in more faithful Fcγ receptor expression. We validated receptor functionality and demonstrated how cytokines modulate their expression. Together, this cross-species Fcγ receptor atlas and humanized mouse model can improve the preclinical evaluation of antibody-based therapeutics.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083461","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 : 2026-01-30DOI: 10.1126/sciimmunol.adv7615
Saad Khan, Mainak Chakraborty, Fei Wu, Nan Chen, Tao Wang, Yi Tao Chan, Azin Sayad, Max Kotlyar, Faisal J. Alibhai, Minna Woo, Ren-Ke Li, Mansoor Husain, Igor Jurisica, Adam J. Gehring, Pamela S. Ohashi, David Furman, Sue Tsai, Shawn Winer, Daniel A. Winer
Dysregulation of the adaptive immune system is a key feature of aging and is associated with age-related chronic diseases and mortality. Here, we find that T cell aging, especially in the CD4 subset, is controlled by B cells. B cells contributed to the age-related reduction of naive CD4 T cells, their differentiation toward immunosenescent T cell subsets, and age-associated T cell receptor clonal restriction. Concurrently, mice lacking B cells displayed improvements in health span and life span. We uncovered a role for B cell–intrinsic insulin receptor signaling in influencing age-related B cell phenotypes that in turn induces CD4 T cell dysfunction, a process that is in part driven by major histocompatibility complex class II. These results identify B cells as critical mediators driving age-associated adaptive immune dysfunction and health-span outcomes and suggest previously unrecognized modalities to manage aging and related health decline.
{"title":"B cells drive CD4 T cell immunosenescence and age-associated health decline","authors":"Saad Khan, Mainak Chakraborty, Fei Wu, Nan Chen, Tao Wang, Yi Tao Chan, Azin Sayad, Max Kotlyar, Faisal J. Alibhai, Minna Woo, Ren-Ke Li, Mansoor Husain, Igor Jurisica, Adam J. Gehring, Pamela S. Ohashi, David Furman, Sue Tsai, Shawn Winer, Daniel A. Winer","doi":"10.1126/sciimmunol.adv7615","DOIUrl":"10.1126/sciimmunol.adv7615","url":null,"abstract":"<div >Dysregulation of the adaptive immune system is a key feature of aging and is associated with age-related chronic diseases and mortality. Here, we find that T cell aging, especially in the CD4 subset, is controlled by B cells. B cells contributed to the age-related reduction of naive CD4 T cells, their differentiation toward immunosenescent T cell subsets, and age-associated T cell receptor clonal restriction. Concurrently, mice lacking B cells displayed improvements in health span and life span. We uncovered a role for B cell–intrinsic insulin receptor signaling in influencing age-related B cell phenotypes that in turn induces CD4 T cell dysfunction, a process that is in part driven by major histocompatibility complex class II. These results identify B cells as critical mediators driving age-associated adaptive immune dysfunction and health-span outcomes and suggest previously unrecognized modalities to manage aging and related health decline.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083460","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 : 2026-01-27DOI: 10.1126/sciimmunol.aed7439
Patrick Fernandes Rodrigues, Shitong Wu, Tihana Trsan, Bishan Bhattarai, Santosh K Panda, José Luís Fachi, Marina Cella, Marco Colonna
How tolerogenic dendritic cell (DC) lineages are established to prevent inappropriate immune responses to commensals and food antigens remains unclear. We identify RORγt+ DCs in mice as a distinct lymphoid-derived lineage to safeguard intestinal tolerance. Using lineage tracing and single-cell transcriptomics, we unveiled bone marrow-resident Rorc(t)+ progenitors, which include a RORγt+ innate lymphoid progenitor (RILP) that generates both ILC3s and RORγt+ DCs, and a pre-RORγt+ DC precursor committed exclusively to the RORγt+ DC lineage. RORγt+ DC development required the Rorc +7 kb enhancer, whose accessibility was ensured by the repressors REV-ERBα and REV-ERBβ, and depended on the transcription factors PRDM16 and PU.1 for lineage commitment. Loss of any of these regulators abrogated RORγt+ DC differentiation, reduced peripheral regulatory T (Treg) cell induction, and skewed toward T helper 2 responses. Together, these findings define murine RORγt+ DCs as a lymphoid-derived lineage whose enhancer- and transcription factor-driven development is essential for peripheral Treg cell-mediated immune homeostasis.
{"title":"RORγt<sup>+</sup> dendritic cells are a distinct lymphoid-derived lineage.","authors":"Patrick Fernandes Rodrigues, Shitong Wu, Tihana Trsan, Bishan Bhattarai, Santosh K Panda, José Luís Fachi, Marina Cella, Marco Colonna","doi":"10.1126/sciimmunol.aed7439","DOIUrl":"https://doi.org/10.1126/sciimmunol.aed7439","url":null,"abstract":"<p><p>How tolerogenic dendritic cell (DC) lineages are established to prevent inappropriate immune responses to commensals and food antigens remains unclear. We identify RORγt<sup>+</sup> DCs in mice as a distinct lymphoid-derived lineage to safeguard intestinal tolerance. Using lineage tracing and single-cell transcriptomics, we unveiled bone marrow-resident <i>Rorc(t)</i><sup>+</sup> progenitors, which include a RORγt<sup>+</sup> innate lymphoid progenitor (RILP) that generates both ILC3s and RORγt<sup>+</sup> DCs, and a pre-RORγt<sup>+</sup> DC precursor committed exclusively to the RORγt<sup>+</sup> DC lineage. RORγt<sup>+</sup> DC development required the <i>Rorc</i> +7 kb enhancer, whose accessibility was ensured by the repressors REV-ERBα and REV-ERBβ, and depended on the transcription factors PRDM16 and PU.1 for lineage commitment. Loss of any of these regulators abrogated RORγt<sup>+</sup> DC differentiation, reduced peripheral regulatory T (T<sub>reg</sub>) cell induction, and skewed toward T helper 2 responses. Together, these findings define murine RORγt<sup>+</sup> DCs as a lymphoid-derived lineage whose enhancer- and transcription factor-driven development is essential for peripheral T<sub>reg</sub> cell-mediated immune homeostasis.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":" ","pages":"eaed7439"},"PeriodicalIF":16.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053635","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 : 2026-01-23DOI: 10.1126/sciimmunol.adu9280
Louise M. C. Webb, Helena A. Carslaw, Jessica James, Emily M. Watson, Silvia Innocentin, Jayalini Assalaarachchi, Sigrid Fra-Bido, Isabel San Martin Molina, Stephane M. Guillaume, Sam Woolliscroft, Alice R. Burton, Grant M. Kennedy, Michelle A. Linterman
T follicular helper (TFH) cells are essential for germinal center (GC) formation and long-lived humoral immunity. Here, we used an Il21 fate mapping (Il21-fm) strategy to remove TFH cells from established GCs to disentangle their function from that of other T cells in a temporal manner. We confirm their role in driving proliferation and positive selection of GC B cells but show that GCs can survive the transient absence of TFH cells. After ablation of TFH cells, both the GC response and affinity maturation recover via ingress of new TFH cells. Despite recovery of the B cell response, TFH cell numbers are never fully restored. This feeds through into the T cell memory response, resulting in diminished recall GC responses. This work shows an unappreciated resilience of primary GC responses to perturbations in TFH cells and demonstrates critical memory T cell generation during this phase.
{"title":"Transient disruption of T cell help impairs germinal center dynamics and memory responses","authors":"Louise M. C. Webb, Helena A. Carslaw, Jessica James, Emily M. Watson, Silvia Innocentin, Jayalini Assalaarachchi, Sigrid Fra-Bido, Isabel San Martin Molina, Stephane M. Guillaume, Sam Woolliscroft, Alice R. Burton, Grant M. Kennedy, Michelle A. Linterman","doi":"10.1126/sciimmunol.adu9280","DOIUrl":"10.1126/sciimmunol.adu9280","url":null,"abstract":"<div >T follicular helper (T<sub>FH</sub>) cells are essential for germinal center (GC) formation and long-lived humoral immunity. Here, we used an <i>Il21</i> fate mapping (Il21-fm) strategy to remove T<sub>FH</sub> cells from established GCs to disentangle their function from that of other T cells in a temporal manner. We confirm their role in driving proliferation and positive selection of GC B cells but show that GCs can survive the transient absence of T<sub>FH</sub> cells. After ablation of T<sub>FH</sub> cells, both the GC response and affinity maturation recover via ingress of new T<sub>FH</sub> cells. Despite recovery of the B cell response, T<sub>FH</sub> cell numbers are never fully restored. This feeds through into the T cell memory response, resulting in diminished recall GC responses. This work shows an unappreciated resilience of primary GC responses to perturbations in T<sub>FH</sub> cells and demonstrates critical memory T cell generation during this phase.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027660","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 : 2026-01-23DOI: 10.1126/sciimmunol.adk1673
Helen Stölting, April L. Raftery, Simone A. Walker, Eimear N. Rutherford, Mindy L. Gore, Yue Huang, Franz Puttur, Laura Yates, Sejal Saglani, Clare M. Lloyd
Hormonal disruptions are associated with poor asthma control in females, yet how these phenomena are linked remains unknown. Here, we investigated distinct allergen-induced immune responses between the sexes during maturation. By 6 weeks of life, female mice exposed to the aeroallergen house dust mite (HDM) from postnatal day 7 exhibited stronger type 2 (T2) immune responses and higher lung interleukin-33 (IL-33) than males. IL-33 administration to HDM-sensitized males was sufficient to augment T2 immunity and up-regulated epidermal growth factor receptor (EGFR) on T helper 2 (TH2) cells. EGFR inhibition abrogated T2 cytokine production in vitro. In vivo, EGFR inhibition reduced T2 immunity in females only, thereby abolishing any sex differences. 17β-estradiol (E2) heightened lung Il33 expression and T2 responses of HDM-sensitized males, akin to levels in females. EGFR’s ability to drive sex differences in lung T2 responses downstream of E2 and IL-33 may link hormonal disruptions to poor asthma control.
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