Joona Sarkkinen, Dawit A. Yohannes, Nea Kreivi, Pia Dürnsteiner, Alexandra Elsakova, Jani Huuhtanen, Kirsten Nowlan, Goran Kurdo, Riikka Linden, Mika Saarela, Pentti J. Tienari, Eliisa Kekäläinen, Maria Perdomo, Sini M. Laakso
{"title":"Altered immune landscape of cervical lymph nodes reveals Epstein-Barr virus signature in multiple sclerosis","authors":"Joona Sarkkinen, Dawit A. Yohannes, Nea Kreivi, Pia Dürnsteiner, Alexandra Elsakova, Jani Huuhtanen, Kirsten Nowlan, Goran Kurdo, Riikka Linden, Mika Saarela, Pentti J. Tienari, Eliisa Kekäläinen, Maria Perdomo, Sini M. Laakso","doi":"10.1126/sciimmunol.adl3604","DOIUrl":"https://doi.org/10.1126/sciimmunol.adl3604","url":null,"abstract":"Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and Epstein-Barr virus (EBV) infection is a prerequisite for developing the disease. However, the pathogenic mechanisms that lead to MS remain to be determined. Here, we characterized the immune landscape of deep cervical lymph nodes (dcLNs) in newly diagnosed untreated patients with MS (pwMS) using fine-needle aspirations. By combining single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing, we observed increased memory B cells and reduced germinal center B cells with decreased clonality in pwMS. Double-negative memory B cells were increased in pwMS that transcriptionally resembled B cells with a lytic EBV infection. Moreover, EBV-targeting memory CD8 T cells were detected in a subset of pwMS. We also detected increased EBV DNA in dcLNs and elevated viral loads in patient saliva. These findings suggest that EBV-driven B cell dysregulation is a critical mechanism in MS pathogenesis.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"29 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463192","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}
Justin B. Zhang, Priyanka Chaurasia, Angela Nguyen, Zijian Huang, Trang T. Nguyen, Hui Xu, Mai T. Tran, Hugh H. Reid, Claerwen M. Jones, Stefan A. Schattgen, Daniel Thiele, Paul G. Thomas, Jeanette Rientjes, Kim L. Good-Jacobson, Roland Ruscher, Dene R. Littler, Jamie Rossjohn, Pirooz Zareie, Nicole L. La Gruta
{"title":"LCK–co-receptor association ensures T cell lineage fidelity and maximizes epitope-specific TCR diversity","authors":"Justin B. Zhang, Priyanka Chaurasia, Angela Nguyen, Zijian Huang, Trang T. Nguyen, Hui Xu, Mai T. Tran, Hugh H. Reid, Claerwen M. Jones, Stefan A. Schattgen, Daniel Thiele, Paul G. Thomas, Jeanette Rientjes, Kim L. Good-Jacobson, Roland Ruscher, Dene R. Littler, Jamie Rossjohn, Pirooz Zareie, Nicole L. La Gruta","doi":"10.1126/sciimmunol.adp5016","DOIUrl":"https://doi.org/10.1126/sciimmunol.adp5016","url":null,"abstract":"The interaction between the CD4/CD8 co-receptors and LCK (an Src family tyrosine kinase) is thought to augment T cell activation upon recognition of peptide-loaded major histocompatibility complexes (pMHCs). How this interaction influences antigen-specific T cell development is unclear however, as is its impact on naïve and immune antigen-specific T cell repertoires. In mice expressing mutated endogenous LCK unable to bind co-receptors (LCK <jats:sup>FREE</jats:sup> mice), we show that influenza A virus (IAV)–derived pMHC-specific CD8 and CD4 T cell responses had a significantly narrowed T cell receptor (TCR) repertoire, favoring high-affinity TCRs. This narrowing was established during T cell development and was exacerbated after viral infection. The dissociation of LCK from co-receptors also resulted in the redirection of CD4-fated T cells to the CD8 lineage, with expanded pMHCII-specific cytotoxic CD8 T cells observed after IAV infection. Thus, LCK–co-receptor association is critical for ensuring T cell lineage fidelity and maximizing antigen-specific T cell repertoire diversity.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"24 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463092","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}
Joona Sarkkinen, Dawit A. Yohannes, Nea Kreivi, Pia Dürnsteiner, Alexandra Elsakova, Jani Huuhtanen, Kirsten Nowlan, Goran Kurdo, Riikka Linden, Mika Saarela, Pentti J. Tienari, Eliisa Kekäläinen, Maria Perdomo, Sini M. Laakso
{"title":"Altered immune landscape of cervical lymph nodes reveals Epstein-Barr virus signature in multiple sclerosis","authors":"Joona Sarkkinen, Dawit A. Yohannes, Nea Kreivi, Pia Dürnsteiner, Alexandra Elsakova, Jani Huuhtanen, Kirsten Nowlan, Goran Kurdo, Riikka Linden, Mika Saarela, Pentti J. Tienari, Eliisa Kekäläinen, Maria Perdomo, Sini M. Laakso","doi":"","DOIUrl":"","url":null,"abstract":"<div >Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and Epstein-Barr virus (EBV) infection is a prerequisite for developing the disease. However, the pathogenic mechanisms that lead to MS remain to be determined. Here, we characterized the immune landscape of deep cervical lymph nodes (dcLNs) in newly diagnosed untreated patients with MS (pwMS) using fine-needle aspirations. By combining single-cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing, we observed increased memory B cells and reduced germinal center B cells with decreased clonality in pwMS. Double-negative memory B cells were increased in pwMS that transcriptionally resembled B cells with a lytic EBV infection. Moreover, EBV-targeting memory CD8 T cells were detected in a subset of pwMS. We also detected increased EBV DNA in dcLNs and elevated viral loads in patient saliva. These findings suggest that EBV-driven B cell dysregulation is a critical mechanism in MS pathogenesis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466336","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}
Justin B. Zhang, Priyanka Chaurasia, Angela Nguyen, Zijian Huang, Trang T. Nguyen, Hui Xu, Mai T. Tran, Hugh H. Reid, Claerwen M. Jones, Stefan A. Schattgen, Daniel Thiele, Paul G. Thomas, Jeanette Rientjes, Kim L. Good-Jacobson, Roland Ruscher, Dene R. Littler, Jamie Rossjohn, Pirooz Zareie, Nicole L. La Gruta
{"title":"LCK–co-receptor association ensures T cell lineage fidelity and maximizes epitope-specific TCR diversity","authors":"Justin B. Zhang, Priyanka Chaurasia, Angela Nguyen, Zijian Huang, Trang T. Nguyen, Hui Xu, Mai T. Tran, Hugh H. Reid, Claerwen M. Jones, Stefan A. Schattgen, Daniel Thiele, Paul G. Thomas, Jeanette Rientjes, Kim L. Good-Jacobson, Roland Ruscher, Dene R. Littler, Jamie Rossjohn, Pirooz Zareie, Nicole L. La Gruta","doi":"","DOIUrl":"","url":null,"abstract":"<div >The interaction between the CD4/CD8 co-receptors and LCK (an Src family tyrosine kinase) is thought to augment T cell activation upon recognition of peptide-loaded major histocompatibility complexes (pMHCs). How this interaction influences antigen-specific T cell development is unclear however, as is its impact on naïve and immune antigen-specific T cell repertoires. In mice expressing mutated endogenous LCK unable to bind co-receptors (LCK<sup>FREE</sup> mice), we show that influenza A virus (IAV)–derived pMHC-specific CD8 and CD4 T cell responses had a significantly narrowed T cell receptor (TCR) repertoire, favoring high-affinity TCRs. This narrowing was established during T cell development and was exacerbated after viral infection. The dissociation of LCK from co-receptors also resulted in the redirection of CD4-fated T cells to the CD8 lineage, with expanded pMHCII-specific cytotoxic CD8 T cells observed after IAV infection. Thus, LCK–co-receptor association is critical for ensuring T cell lineage fidelity and maximizing antigen-specific T cell repertoire diversity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp5016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466319","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}
Peng Shao, Regina M. Antonetti, Tina Arkee, Emma L. Hornick, Hai Hui Xue, Gail A. Bishop, Noah S. Butler
{"title":"TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R–BCL6 signaling nexus","authors":"Peng Shao, Regina M. Antonetti, Tina Arkee, Emma L. Hornick, Hai Hui Xue, Gail A. Bishop, Noah S. Butler","doi":"","DOIUrl":"","url":null,"abstract":"<div >CD4<sup>+</sup> T follicular helper (T<sub>FH</sub>) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate T<sub>FH</sub> cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for T<sub>FH</sub> cell differentiation and function during systemic inflammatory infections. Loss of CD4<sup>+</sup> T cell–intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for T<sub>FH</sub> cell initiation and instead augmented T<sub>H</sub>1 development and function. TRAF3-deficient CD4<sup>+</sup> T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue T<sub>FH</sub> cell differentiation. Human CD4<sup>+</sup> T cells lacking TRAF3 exhibited impaired T<sub>FH</sub> polarization, supporting a conserved mechanism by which TRAF3 regulates CD4<sup>+</sup> T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the T<sub>FH</sub> cell specification during infection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424394","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":"Linking vaccine adjuvant mechanisms of action to function.","authors":"Elana Ben-Akiva, Asheley Chapman, Tianyang Mao, Darrell J Irvine","doi":"10.1126/sciimmunol.ado5937","DOIUrl":"https://doi.org/10.1126/sciimmunol.ado5937","url":null,"abstract":"<p><p>Vaccines deliver an immunogen in a manner designed to safely provoke an immune response, leading to the generation of memory T and B cells and long-lived antibody-producing plasma cells. Adjuvants play a critical role in vaccines by controlling how the immune system is exposed to the immunogen and providing inflammatory cues that enable productive immune priming. However, mechanisms of action underlying adjuvant function at the molecular, cell, and tissue levels are diverse and often poorly understood. Here, we review the current understanding of mechanisms of action underlying adjuvants used in subunit protein/polysaccharide vaccines and mRNA vaccines, discuss where possible how these mechanisms of action link to downstream effects on the immune response, and identify knowledge gaps that will be important to fill in order to enable the continued development of more effective adjuvants for challenging pathogens such as HIV and emerging threats.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":"eado5937"},"PeriodicalIF":17.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417149","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}
Peng Shao, Regina M Antonetti, Tina Arkee, Emma L Hornick, Hai Hui Xue, Gail A Bishop, Noah S Butler
{"title":"TRAF3 is critical for initial T follicular helper cell specification via coordination of the IL-6R/IL-2R-BCL6 signaling nexus.","authors":"Peng Shao, Regina M Antonetti, Tina Arkee, Emma L Hornick, Hai Hui Xue, Gail A Bishop, Noah S Butler","doi":"10.1126/sciimmunol.adr0517","DOIUrl":"https://doi.org/10.1126/sciimmunol.adr0517","url":null,"abstract":"<p><p>CD4<sup>+</sup> T follicular helper (T<sub>FH</sub>) cells are essential for orchestrating robust humoral immunity, yet the signals that initiate T<sub>FH</sub> cell differentiation are not fully understood. We identified that the adapter protein TRAF3 was required for T<sub>FH</sub> cell differentiation and function during systemic inflammatory infections. Loss of CD4<sup>+</sup> T cell-intrinsic TRAF3 impaired chromatin remodeling and transcriptional programming essential for T<sub>FH</sub> cell initiation and instead augmented T<sub>H</sub>1 development and function. TRAF3-deficient CD4<sup>+</sup> T cells exhibited altered interleukin-6 (IL-6) and IL-2 responsiveness, which were coupled to failures in BCL6 expression. Enforced expression of either IL-6 receptor or BCL6 or blockade of IL-2 signaling was sufficient to rescue T<sub>FH</sub> cell differentiation. Human CD4<sup>+</sup> T cells lacking TRAF3 exhibited impaired T<sub>FH</sub> polarization, supporting a conserved mechanism by which TRAF3 regulates CD4<sup>+</sup> T cell fate determination. Thus, TRAF3 functions at the nexus of cytokine, transcriptional, and epigenetic nodes that promote the T<sub>FH</sub> cell specification during infection.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":"eadr0517"},"PeriodicalIF":17.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417150","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}
Elana Ben-Akiva, Asheley Chapman, Tianyang Mao, Darrell J. Irvine
{"title":"Linking vaccine adjuvant mechanisms of action to function","authors":"Elana Ben-Akiva, Asheley Chapman, Tianyang Mao, Darrell J. Irvine","doi":"","DOIUrl":"","url":null,"abstract":"<div >Vaccines deliver an immunogen in a manner designed to safely provoke an immune response, leading to the generation of memory T and B cells and long-lived antibody-producing plasma cells. Adjuvants play a critical role in vaccines by controlling how the immune system is exposed to the immunogen and providing inflammatory cues that enable productive immune priming. However, mechanisms of action underlying adjuvant function at the molecular, cell, and tissue levels are diverse and often poorly understood. Here, we review the current understanding of mechanisms of action underlying adjuvants used in subunit protein/polysaccharide vaccines and mRNA vaccines, discuss where possible how these mechanisms of action link to downstream effects on the immune response, and identify knowledge gaps that will be important to fill in order to enable the continued development of more effective adjuvants for challenging pathogens such as HIV and emerging threats.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424387","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}
Raphael Lutz, Alexandra M. Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A. Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M. Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J. Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S. Raab, Simon Haas, Niels Weinhold
{"title":"Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma","authors":"Raphael Lutz, Alexandra M. Poos, Llorenç Solé-Boldo, Lukas John, Johanna Wagner, Nina Prokoph, Marc A. Baertsch, Dominik Vonficht, Subarna Palit, Alexander Brobeil, Gunhild Mechtersheimer, Nina Hildenbrand, Stefan Hemmer, Simon Steiger, Sabrina Horn, Wojciech Pepke, David M. Spranz, Christoph Rehnitz, Pooja Sant, Jan-Philipp Mallm, Mirco J. Friedrich, Philipp Reichert, Stefanie Huhn, Andreas Trumpp, Karsten Rippe, Laleh Haghverdi, Stefan Fröhling, Carsten Müller-Tidow, Daniel Hübschmann, Hartmut Goldschmidt, Gerald Willimsky, Sandra Sauer, Marc S. Raab, Simon Haas, Niels Weinhold","doi":"10.1126/sciimmunol.adp6667","DOIUrl":"https://doi.org/10.1126/sciimmunol.adp6667","url":null,"abstract":"The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As the disease progresses, malignant myeloma cells can evolve to survive outside the bone marrow. However, the processes underlying bone marrow independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell and spatial multiomics analyses of bone marrow–confined intramedullary disease and paired breakout lesions that disrupt the cortical bone. These analyses revealed a distinct cellular microenvironment and architectural features of breakout lesions, characterized by extensive areas of malignant plasma cells interspersed with lesion-specific solitary natural killer and macrophage populations, as well as focal accumulations of immune cell agglomerates. Within these agglomerates, spatially confined T cell clones expanded alongside various immune cells, coinciding with the local genomic evolution of tumor cells. These analyses identify breakout lesions as a hotspot for tumor-immune cell interactions and diversification, representing a key event in myeloma pathogenesis.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"63 10 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258318","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}
Bin Yang, Ophélie Piedfort, Guillem Sanchez-Sanchez, Arnaud Lavergne, Meijiao Gong, Garrie Peng, Ariel Madrigal, Georgios Petrellis, Brunette Katsandegwaza, Lucia Rodriguez Rodriguez, Alexis Balthazar, Sarah J. Meyer, Gert Van Isterdael, Julie Van Duyse, Fabienne Andris, Qiang Bai, Thomas Marichal, Bénédicte Machiels, Lars Nitschke, Hamed S. Najafabadi, Irah L. King, David Vermijlen, Benjamin G. Dewals
{"title":"IL-4 induces CD22 expression to restrain the effector program of virtual memory T cells","authors":"Bin Yang, Ophélie Piedfort, Guillem Sanchez-Sanchez, Arnaud Lavergne, Meijiao Gong, Garrie Peng, Ariel Madrigal, Georgios Petrellis, Brunette Katsandegwaza, Lucia Rodriguez Rodriguez, Alexis Balthazar, Sarah J. Meyer, Gert Van Isterdael, Julie Van Duyse, Fabienne Andris, Qiang Bai, Thomas Marichal, Bénédicte Machiels, Lars Nitschke, Hamed S. Najafabadi, Irah L. King, David Vermijlen, Benjamin G. Dewals","doi":"","DOIUrl":"","url":null,"abstract":"<div >Parasitic helminths induce the production of interleukin-4 (IL-4), which causes the expansion of virtual memory CD8<sup>+</sup> T cells (T<sub>VM</sub> cells), a cell subset that contributes to the control of coinfection with intracellular pathogens. However, the mechanisms regulating IL-4–dependent T<sub>VM</sub> cell activation and expansion remain ill defined. Here, we used single-cell RNA sequencing of CD8<sup>+</sup> T cells to identify pathways that control IL-4–dependent T<sub>VM</sub> cell responses. Gene signature analysis of CD8<sup>+</sup> T cells identified a cell cluster marked by CD22, a canonical regulator of B cell activation, as a selective surface marker of IL-4–induced T<sub>VM</sub> cells. CD22<sup>+</sup> T<sub>VM</sub> cells were enriched for interferon-γ and granzyme A and retained a diverse TCR repertoire while enriched in self-reactive CDR3 sequences. CD22 intrinsically regulated the IL-4–induced CD8<sup>+</sup> T cell effector program, resulting in reduced responsiveness of CD22<sup>+</sup> T<sub>VM</sub> cells and regulatory functions to infection and inflammation. Thus, helminth-induced IL-4 drives the expansion and activation of T<sub>VM</sub> cells that is counterinhibited by CD22.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363129","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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