The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice
IntroductionHumans with gain-of-function (GOF) mutations in STAT1 (Signal Transducer and Activator of Transcription 1), a potent immune regulator, experience frequent infections. About one-third, especially those with DNA-binding domain (DBD) mutations such as T385M, also develop autoimmunity, somet...
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| Format: | Article |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1183273/full |
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| author | Ori Scott Ori Scott Ori Scott Shagana Visuvanathan Emily Reddy Deeqa Mahamed Bin Gu Bin Gu Chaim M. Roifman Chaim M. Roifman Ronald D. Cohn Ronald D. Cohn Ronald D. Cohn Cynthia J. Guidos Cynthia J. Guidos Evgueni A. Ivakine |
| author_facet | Ori Scott Ori Scott Ori Scott Shagana Visuvanathan Emily Reddy Deeqa Mahamed Bin Gu Bin Gu Chaim M. Roifman Chaim M. Roifman Ronald D. Cohn Ronald D. Cohn Ronald D. Cohn Cynthia J. Guidos Cynthia J. Guidos Evgueni A. Ivakine |
| author_sort | Ori Scott |
| collection | DOAJ |
| description | IntroductionHumans with gain-of-function (GOF) mutations in STAT1 (Signal Transducer and Activator of Transcription 1), a potent immune regulator, experience frequent infections. About one-third, especially those with DNA-binding domain (DBD) mutations such as T385M, also develop autoimmunity, sometimes accompanied by increases in T-helper 1 (Th1) and T-follicular helper (Tfh) CD4 effector T cells, resembling those that differentiate following infection-induced STAT1 signaling. However, environmental and molecular mechanisms contributing to autoimmunity in STAT1 GOF patients are not defined. MethodsWe generated Stat1T385M/+ mutant mice to model the immune impacts of STAT1 DBD GOF under specific-pathogen free (SPF) conditions.ResultsStat1T385M/+ lymphocytes had more total Stat1 at baseline and also higher amounts of IFNg-induced pStat1. Young mutants exhibited expansion of Tfh-like cells, while older mutants developed autoimmunity accompanied by increased Tfh-like cells, B cell activation and germinal center (GC) formation. Mutant females exhibited these immune changes sooner and more robustly than males, identifying significant sex effects of Stat1T385M-induced immune dysregulation. Single cell RNA-Seq (scRNA-Seq) analysis revealed that Stat1T385M activated transcription of GC-associated programs in both B and T cells. However, it had the strongest transcriptional impact on T cells, promoting aberrant CD4 T cell activation and imparting both Tfh-like and Th1-like effector programs. DiscussionCollectively, these data demonstrate that in the absence of overt infection, Stat1T385M disrupted naïve CD4 T cell homeostasis and promoted expansion and differentiation of abnormal Tfh/Th1-like helper and GC-like B cells, eventually leading to sex-biased autoimmunity, suggesting a model for STAT1 GOF-induced immune dysregulation and autoimmune sequelae in humans. |
| first_indexed | 2024-03-13T10:28:10Z |
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| id | doaj.art-a92971508e374a85a787e6e51acaca8e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-13T10:28:10Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a92971508e374a85a787e6e51acaca8e2023-05-19T05:03:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-05-011410.3389/fimmu.2023.11832731183273The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free miceOri Scott0Ori Scott1Ori Scott2Shagana Visuvanathan3Emily Reddy4Deeqa Mahamed5Bin Gu6Bin Gu7Chaim M. Roifman8Chaim M. Roifman9Ronald D. Cohn10Ronald D. Cohn11Ronald D. Cohn12Cynthia J. Guidos13Cynthia J. Guidos14Evgueni A. Ivakine15Division of Immunology and Allergy, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON, CanadaProgram for Genetics & Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON, CanadaInstitute of Medical Science, University of Toronto, Toronto, ON, CanadaProgram for Genetics & Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON, CanadaProgram in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, CanadaProgram in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, CanadaDepartment of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, East Lansing, MI, United StatesInstitute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United StatesDivision of Immunology and Allergy, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON, CanadaThe Canadian Centre for Primary Immunodeficiency and The Jeffrey Modell Research Laboratory for the diagnosis of Primary Immunodeficiency, The Hospital for Sick Children, Toronto, ON, CanadaProgram for Genetics & Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON, CanadaInstitute of Medical Science, University of Toronto, Toronto, ON, CanadaDivision of Clinical & Metabolic Genetics, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON, CanadaProgram in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, CanadaDepartment of Immunology, University of Toronto, Toronto, ON, Canada0Department of Physiology, University of Toronto, Toronto, ON, CanadaIntroductionHumans with gain-of-function (GOF) mutations in STAT1 (Signal Transducer and Activator of Transcription 1), a potent immune regulator, experience frequent infections. About one-third, especially those with DNA-binding domain (DBD) mutations such as T385M, also develop autoimmunity, sometimes accompanied by increases in T-helper 1 (Th1) and T-follicular helper (Tfh) CD4 effector T cells, resembling those that differentiate following infection-induced STAT1 signaling. However, environmental and molecular mechanisms contributing to autoimmunity in STAT1 GOF patients are not defined. MethodsWe generated Stat1T385M/+ mutant mice to model the immune impacts of STAT1 DBD GOF under specific-pathogen free (SPF) conditions.ResultsStat1T385M/+ lymphocytes had more total Stat1 at baseline and also higher amounts of IFNg-induced pStat1. Young mutants exhibited expansion of Tfh-like cells, while older mutants developed autoimmunity accompanied by increased Tfh-like cells, B cell activation and germinal center (GC) formation. Mutant females exhibited these immune changes sooner and more robustly than males, identifying significant sex effects of Stat1T385M-induced immune dysregulation. Single cell RNA-Seq (scRNA-Seq) analysis revealed that Stat1T385M activated transcription of GC-associated programs in both B and T cells. However, it had the strongest transcriptional impact on T cells, promoting aberrant CD4 T cell activation and imparting both Tfh-like and Th1-like effector programs. DiscussionCollectively, these data demonstrate that in the absence of overt infection, Stat1T385M disrupted naïve CD4 T cell homeostasis and promoted expansion and differentiation of abnormal Tfh/Th1-like helper and GC-like B cells, eventually leading to sex-biased autoimmunity, suggesting a model for STAT1 GOF-induced immune dysregulation and autoimmune sequelae in humans. https://www.frontiersin.org/articles/10.3389/fimmu.2023.1183273/fullSTAT1autoimmunitychronic activationT helperimmune dysregulationSpecific pathogen free (SPF) |
| spellingShingle | Ori Scott Ori Scott Ori Scott Shagana Visuvanathan Emily Reddy Deeqa Mahamed Bin Gu Bin Gu Chaim M. Roifman Chaim M. Roifman Ronald D. Cohn Ronald D. Cohn Ronald D. Cohn Cynthia J. Guidos Cynthia J. Guidos Evgueni A. Ivakine The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice Frontiers in Immunology STAT1 autoimmunity chronic activation T helper immune dysregulation Specific pathogen free (SPF) |
| title | The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice |
| title_full | The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice |
| title_fullStr | The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice |
| title_full_unstemmed | The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice |
| title_short | The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice |
| title_sort | human stat1 gain of function t385m mutation causes expansion of activated t follicular helper t helper 1 like cd4 t cells and sex biased autoimmunity in specific pathogen free mice |
| topic | STAT1 autoimmunity chronic activation T helper immune dysregulation Specific pathogen free (SPF) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1183273/full |
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