title: Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.
abstract: Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.
authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia s.tangye@garvan.org.au c.ma@garvan.org.au.
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authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
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authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
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authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
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authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
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authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
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authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
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authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
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authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163,75270 Paris, France Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, 75015 Paris, France St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Imagine Institute, Necker Medical School, Paris Descartes University, 75270 Paris, France.
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authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163,75270 Paris, France Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, 75015 Paris, France Imagine Institute, Necker Medical School, Paris Descartes University, 75270 Paris, France.
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authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163,75270 Paris, France Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, 75015 Paris, France St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Imagine Institute, Necker Medical School, Paris Descartes University, 75270 Paris, France.
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authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163,75270 Paris, France St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Imagine Institute, Necker Medical School, Paris Descartes University, 75270 Paris, France.
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authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163,75270 Paris, France Pediatric Hematology and Immunology Unit, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, 75015 Paris, France St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 Howard Hughes Medical Institute, New York, NY 10065 Imagine Institute, Necker Medical School, Paris Descartes University, 75270 Paris, France.
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authors.affiliation: Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
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mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008297:Male; D009154:Mutation; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000943:Antigens, Differentiation; C556062:IL10 protein, mouse; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10