Pub Date : 2025-03-07DOI: 10.1126/sciimmunol.adx0218
Rachael A. Clark
Mouse anti-RNA antibodies triggered by gut E. gallinarum correlate with self-RNA autoantibodies and lupus severity in humans.
{"title":"Trouble at the border: An invading gut bacterium can break tolerance to self-RNA","authors":"Rachael A. Clark","doi":"10.1126/sciimmunol.adx0218","DOIUrl":"https://doi.org/10.1126/sciimmunol.adx0218","url":null,"abstract":"Mouse anti-RNA antibodies triggered by gut <jats:italic>E. gallinarum</jats:italic> correlate with self-RNA autoantibodies and lupus severity in humans.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"127 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575441","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}
Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry
Although checkpoint blockade temporarily improves exhausted CD8 T (Tex) cell function, the underlying Tex epigenetic landscape remains largely unchanged, preventing durable Tex “reinvigoration” in cancer and chronic infections. The transcription factor TOX initiates Tex epigenetic programming, yet it remains unclear whether TOX continually preserves Tex biology after Tex establishment. Here, we demonstrated that induced TOX ablation in committed Tex cells resulted in apoptotic-driven loss of Tex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed Tex cells. Moreover, TOX removal endows established Tex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established Tex cells acts as a durable epigenetic barrier reinforcing the Tex developmental fate. TOX manipulation even after Tex establishment could therefore provide therapeutic opportunities to rewire Tex cells in chronic infections or cancer.
{"title":"Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate","authors":"Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry","doi":"","DOIUrl":"","url":null,"abstract":"<div >Although checkpoint blockade temporarily improves exhausted CD8 T (T<sub>ex</sub>) cell function, the underlying T<sub>ex</sub> epigenetic landscape remains largely unchanged, preventing durable T<sub>ex</sub> “reinvigoration” in cancer and chronic infections. The transcription factor TOX initiates T<sub>ex</sub> epigenetic programming, yet it remains unclear whether TOX continually preserves T<sub>ex</sub> biology after T<sub>ex</sub> establishment. Here, we demonstrated that induced TOX ablation in committed T<sub>ex</sub> cells resulted in apoptotic-driven loss of T<sub>ex</sub> cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed T<sub>ex</sub> cells. Moreover, TOX removal endows established T<sub>ex</sub> cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established T<sub>ex</sub> cells acts as a durable epigenetic barrier reinforcing the T<sub>ex</sub> developmental fate. TOX manipulation even after T<sub>ex</sub> establishment could therefore provide therapeutic opportunities to rewire T<sub>ex</sub> cells in chronic infections or cancer.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583692","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 : 2025-03-07DOI: 10.1126/sciimmunol.adx0208
Isabelle Leo, Etienne Caron
Specific MBP-derived self-peptides promote immune tolerance in the CNS and induce an unconventional regulatory T cell response.
{"title":"MBPeace treaty: How myelin self-peptides broker CNS tolerance.","authors":"Isabelle Leo, Etienne Caron","doi":"10.1126/sciimmunol.adx0208","DOIUrl":"https://doi.org/10.1126/sciimmunol.adx0208","url":null,"abstract":"<p><p>Specific MBP-derived self-peptides promote immune tolerance in the CNS and induce an unconventional regulatory T cell response.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 105","pages":"eadx0208"},"PeriodicalIF":17.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575986","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 : 2025-03-07DOI: 10.1126/sciimmunol.ado3032
Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry
Although checkpoint blockade temporarily improves exhausted CD8 T (T ex ) cell function, the underlying T ex epigenetic landscape remains largely unchanged, preventing durable T ex “reinvigoration” in cancer and chronic infections. The transcription factor TOX initiates T ex epigenetic programming, yet it remains unclear whether TOX continually preserves T ex biology after T ex establishment. Here, we demonstrated that induced TOX ablation in committed T ex cells resulted in apoptotic-driven loss of T ex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed T ex cells. Moreover, TOX removal endows established T ex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established T ex cells acts as a durable epigenetic barrier reinforcing the T ex developmental fate. TOX manipulation even after T ex establishment could therefore provide therapeutic opportunities to rewire T ex cells in chronic infections or cancer.
{"title":"Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate","authors":"Yinghui J. Huang, Shin Foong Ngiow, Amy E. Baxter, Sasikanth Manne, Simone L. Park, Jennifer E. Wu, Omar Khan, Josephine R. Giles, E. John Wherry","doi":"10.1126/sciimmunol.ado3032","DOIUrl":"https://doi.org/10.1126/sciimmunol.ado3032","url":null,"abstract":"Although checkpoint blockade temporarily improves exhausted CD8 T (T <jats:sub>ex</jats:sub> ) cell function, the underlying T <jats:sub>ex</jats:sub> epigenetic landscape remains largely unchanged, preventing durable T <jats:sub>ex</jats:sub> “reinvigoration” in cancer and chronic infections. The transcription factor TOX initiates T <jats:sub>ex</jats:sub> epigenetic programming, yet it remains unclear whether TOX continually preserves T <jats:sub>ex</jats:sub> biology after T <jats:sub>ex</jats:sub> establishment. Here, we demonstrated that induced TOX ablation in committed T <jats:sub>ex</jats:sub> cells resulted in apoptotic-driven loss of T <jats:sub>ex</jats:sub> cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed T <jats:sub>ex</jats:sub> cells. Moreover, TOX removal endows established T <jats:sub>ex</jats:sub> cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established T <jats:sub>ex</jats:sub> cells acts as a durable epigenetic barrier reinforcing the T <jats:sub>ex</jats:sub> developmental fate. TOX manipulation even after T <jats:sub>ex</jats:sub> establishment could therefore provide therapeutic opportunities to rewire T <jats:sub>ex</jats:sub> cells in chronic infections or cancer.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"30 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575440","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 : 2025-02-28DOI: 10.1126/sciimmunol.adq4973
Vadim A. Klenchin, Natasha M. Clark, Nida K. Keles, Saverio Capuano, Rosemarie Mason, Guangping Gao, Aimee Broman, Emek Kose, Taina T. Immonen, Christine M. Fennessey, Brandon F. Keele, Jeffrey D. Lifson, Mario Roederer, Matthew R. Gardner, David T. Evans
An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here, we show that adeno-associated virus (AAV) delivery of two rhesus macaque antibodies to the simian immunodeficiency virus (SIV) envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIV mac 239M after discontinuing suppressive ART. After AAV administration, sustained antibody expression with minimal antidrug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within 2 weeks in all control animals but remained <15 copies per milliliter in plasma for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals that rebounded with delayed kinetics exhibited restricted clonal diversity and antibody escape mutations in Env. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.
{"title":"Adeno-associated viral delivery of Env-specific antibodies prevents SIV rebound after discontinuing antiretroviral therapy","authors":"Vadim A. Klenchin, Natasha M. Clark, Nida K. Keles, Saverio Capuano, Rosemarie Mason, Guangping Gao, Aimee Broman, Emek Kose, Taina T. Immonen, Christine M. Fennessey, Brandon F. Keele, Jeffrey D. Lifson, Mario Roederer, Matthew R. Gardner, David T. Evans","doi":"10.1126/sciimmunol.adq4973","DOIUrl":"https://doi.org/10.1126/sciimmunol.adq4973","url":null,"abstract":"An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here, we show that adeno-associated virus (AAV) delivery of two rhesus macaque antibodies to the simian immunodeficiency virus (SIV) envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIV <jats:sub>mac</jats:sub> 239M after discontinuing suppressive ART. After AAV administration, sustained antibody expression with minimal antidrug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within 2 weeks in all control animals but remained <15 copies per milliliter in plasma for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals that rebounded with delayed kinetics exhibited restricted clonal diversity and antibody escape mutations in Env. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"85 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518147","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}
Vadim A. Klenchin, Natasha M. Clark, Nida K. Keles, Saverio Capuano III, Rosemarie Mason, Guangping Gao, Aimee Broman, Emek Kose, Taina T. Immonen, Christine M. Fennessey, Brandon F. Keele, Jeffrey D. Lifson, Mario Roederer, Matthew R. Gardner, David T. Evans
An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here, we show that adeno-associated virus (AAV) delivery of two rhesus macaque antibodies to the simian immunodeficiency virus (SIV) envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIVmac239M after discontinuing suppressive ART. After AAV administration, sustained antibody expression with minimal antidrug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within 2 weeks in all control animals but remained <15 copies per milliliter in plasma for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals that rebounded with delayed kinetics exhibited restricted clonal diversity and antibody escape mutations in Env. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.
{"title":"Adeno-associated viral delivery of Env-specific antibodies prevents SIV rebound after discontinuing antiretroviral therapy","authors":"Vadim A. Klenchin, Natasha M. Clark, Nida K. Keles, Saverio Capuano III, Rosemarie Mason, Guangping Gao, Aimee Broman, Emek Kose, Taina T. Immonen, Christine M. Fennessey, Brandon F. Keele, Jeffrey D. Lifson, Mario Roederer, Matthew R. Gardner, David T. Evans","doi":"","DOIUrl":"","url":null,"abstract":"<div >An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here, we show that adeno-associated virus (AAV) delivery of two rhesus macaque antibodies to the simian immunodeficiency virus (SIV) envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIV<sub>mac</sub>239M after discontinuing suppressive ART. After AAV administration, sustained antibody expression with minimal antidrug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within 2 weeks in all control animals but remained <15 copies per milliliter in plasma for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals that rebounded with delayed kinetics exhibited restricted clonal diversity and antibody escape mutations in Env. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adq4973","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527749","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 : 2025-02-21DOI: 10.1126/sciimmunol.adl3604
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
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.
{"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}
Pub Date : 2025-02-21DOI: 10.1126/sciimmunol.adp5016
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
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 FREE 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.
{"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
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.
{"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
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 (LCKFREE 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.
{"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}
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