ArticleThe Journal of experimental medicine2016
Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.
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Article in The Journal of experimental medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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58citing papers in PubMed
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58 citing papers in PubMed, 86 citations in OpenAlex.
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- A unified network systems approach uncovers a core program underlying T follicular helper cell differentiation.Nature communications · 2026Article
- Inherited human CARD9 deficiency impairs lymphoid cell, but not fibroblast, IL-17-mediated immunity.JCI insight · 2026Article
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- Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4The Journal of allergy and clinical immunology · 2025Article
- Functional validation of a novel STAT3 'variant of unknown significance' identifies a new case of STAT3 GOF syndrome and reveals broad immune cell defects.Clinical and experimental immunology · 2025Article
- Interacting roles of gut microbiota and T cells in the development of autoimmune hepatitis.Frontiers in immunology · 2025Review
- Qualitative Immunoglobulin Deficiency Causes Bacterial Infections in Patients with STAT1 Gain-of-Function Mutations.Journal of clinical immunology · 2024Article
- Unraveling the unphosphorylated STAT3-unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome.Frontiers in immunology · 2024Article
- Inborn errors of human B cell development, differentiation, and function.The Journal of experimental medicine · 2023Review
- Inborn Errors of Immunity: A Role for Functional Testing and Flow Cytometry in Aiding Clinical Diagnosis.The journal of allergy and clinical immunology. In practice · 2023Article
- The Th17/IL-17 Axis and Host Defense Against Fungal Infections.The journal of allergy and clinical immunology. In practice · 2023Review
- Deficiencies and Dysregulation of STAT Pathways That Drive Inborn Errors of Immunity: Lessons from Patients and Mouse Models of Disease.Journal of immunology (Baltimore, Md. : 1950) · 2023Review
- The ups and downs of STAT3 function: too much, too little and human immune dysregulation.Clinical and experimental immunology · 2023Review
- Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation.Nature communications · 2022Article
- Human T-bet governs the generation of a distinct subset of CD11cScience immunology · 2022Article
- Human autoantibodies underlying infectious diseases.The Journal of experimental medicine · 2022Article
- MALT1 regulates Th2 and Th17 differentiationFrontiers in immunology · 2022Article
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Authors and funding
46 authors at 20 institutions in 11 countries.
Cindy S MaImmunology 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.
Natalie WongImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
Geetha RaoImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
Akira NguyenImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
Danielle T AveryImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
Kathryn PayneImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
James TorpyImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
Patrick O'YoungImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
Elissa DeenickImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
Jacinta BustamanteLaboratory 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.
Anne PuelLaboratory 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.
Satoshi OkadaDepartment of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.
Masao KobayashiDepartment of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.
Ruben Martinez-BarricarteSt Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
Michael ElliottSydney Medical School, University of Sydney, Sydney 2006, Australia Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Camperdown 2050, Australia.
Sara Sebnem KilicDepartment of Pediatric Immunology, Uludag University Medical Faculty, 16059 Görükle, Bursa, Turkey.
Jamila El BaghdadiGenetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco.
Yoshiyuki MinegishiDivision of Molecular Medicine, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.
Aziz BousfihaClinical Immunology Unit, Department of Pediatrics, CHU Ibn Rochd, Casablanca, 20100, Morocco.
Nic RobertsonPrimary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.
Sophie HambletonPrimary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.
Peter D ArkwrightUniversity of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, England, UK.
Martyn FrenchDepartment of Clinical Immunology, Royal Perth Hospital, Perth 6009, Australia School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, Australia.
Annaliesse K BlincoeStarship Children's Hospital, Auckland 1023, New Zealand.
Peter HsuChildren's Hospital at Westmead, Westmead 2145, Australia.
Dianne E CampbellChildren's Hospital at Westmead, Westmead 2145, Australia.
Michael O StormonChildren's Hospital at Westmead, Westmead 2145, Australia.
Melanie WongChildren's Hospital at Westmead, Westmead 2145, Australia.
Stephen AdelsteinSydney Medical School, University of Sydney, Sydney 2006, Australia Clinical Immunology, Royal Prince Alfred Hospital, Camperdown 2050, Australia.
David A FulcherDepartment of Immunology, Westmead Hospital, University of Sydney, Westmead 2145, Australia.
Matthew C CookAustralian National University Medical School, Australian National University, Canberra 0200, Australia John Curtin School of Medical Research, Australian National University, Canberra 0200, Australia Department of Immunology, The Canberra Hospital, Garran 2605, Australia Pediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.
Polina StepenskyPediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.
Kaan BoztugCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, A-1090 Vienna, Austria Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, A-1090 Vienna, Austria.
Rita BeierPediatric Haematology and Oncology, University Hospital Essen, 45147 Essen, Germany.
Aydan IkincioğullariDepartment of Pediatric Immunology and Allergy, Ankara University Medical School, 06620 Ankara, Turkey.
John B ZieglerUniversity of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.
Paul GrayUniversity of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.
Capucine PicardLaboratory 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.
Stéphanie Boisson-DupuisLaboratory 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.
Tri Giang PhanImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
Bodo GrimbacherCenter for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.
Klaus WarnatzCenter for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.
Steven M HollandLaboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Gulbu UzelLaboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Jean-Laurent CasanovaLaboratory 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.
Stuart G TangyeImmunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
Garvan Institute of Medical Research · AUChildren's Hospital at Westmead · AUInserm · FRThe University of Sydney · AUHiroshima University · JPNational Institutes of Health · USNewcastle University · GBUniversity of Freiburg · DEUNSW Sydney · AUAnkara University · TRAustralian National University · AUAustrian Academy of Sciences · ATBursa Uludağ Üni̇versi̇tesi̇ · TRCentre Hospitalier Universitaire Ibn Rochd · MAEssen University Hospital · DEHadassah Medical Center · ILHôpital Militaire Moulay Ismail · MAHoward Hughes Medical Institute · USRockefeller University · USStarship Children's Health · NZ
Funding
TRANSFORMING TRANSLATIONAL SCIENCE AND EDUCATION TO BENEFIT HUMAN HEALTHUL1RR024143 · NCRR · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY · 2006 to 2011
$49.1MNCRR NIH HHS UL1 RR024143
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.
Indexed as
Antigens, DifferentiationCell DifferentiationFemaleHumansInterleukin-10MaleMutationSTAT1 Transcription FactorSTAT3 Transcription FactorTh17 CellsTh1 CellsTh2 CellsAntigens, DifferentiationIL10 protein, mouseInterleukin-10STAT1 protein, humanSTAT1 Transcription FactorSTAT3 protein, humanSTAT3 Transcription Factor
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