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    The Journal of experimental medicine. 2016 Jul 11. pii: jem.20151467. doi: 10.1084/jem.20151467
    Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.
    Ma CS1,  Wong N2,  Rao G3,  Nguyen A4,  Avery DT5,  Payne K6,  Torpy J7,  O'Young P8,  Deenick E9,  Bustamante J10,  Puel A11,  Okada S12,  Kobayashi M13,  Martinez-Barricarte R14,  Elliott M15,  Sebnem Kilic S16,  El Baghdadi J17,  Minegishi Y18,  Bousfiha A19,  Robertson N20,  Hambleton S21,  Arkwright PD22,  French M23,  Blincoe AK24,  Hsu P25,  Campbell DE26,  Stormon MO27,  Wong M28,  Adelstein S29,  Fulcher DA30,  Cook MC31,  Stepensky P32,  Boztug K33,  Beier R34,  Ikincioğullari A35,  Ziegler JB36,  Gray P37,  Picard C38,  Boisson-Dupuis S39,  Phan TG40,  Grimbacher B41,  Warnatz K42,  Holland SM43,  Uzel G44,  Casanova JL45,  Tangye SG46
    Author information
    1Immunology 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.
    2Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
    3Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
    4Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
    5Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
    6Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
    7Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
    8Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
    9Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
    10Laboratory 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.
    11Laboratory 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.
    12Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.
    13Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.
    14St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
    15Sydney Medical School, University of Sydney, Sydney 2006, Australia Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Camperdown 2050, Australia.
    16Department of Pediatric Immunology, Uludag University Medical Faculty, 16059 Görükle, Bursa, Turkey.
    17Genetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco.
    18Division of Molecular Medicine, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.
    19Clinical Immunology Unit, Department of Pediatrics, CHU Ibn Rochd, Casablanca, 20100, Morocco.
    20Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.
    21Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.
    22University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, England, UK.
    23Department of Clinical Immunology, Royal Perth Hospital, Perth 6009, Australia School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, Australia.
    24Starship Children's Hospital, Auckland 1023, New Zealand.
    25Children's Hospital at Westmead, Westmead 2145, Australia.
    26Children's Hospital at Westmead, Westmead 2145, Australia.
    27Children's Hospital at Westmead, Westmead 2145, Australia.
    28Children's Hospital at Westmead, Westmead 2145, Australia.
    29Sydney Medical School, University of Sydney, Sydney 2006, Australia Clinical Immunology, Royal Prince Alfred Hospital, Camperdown 2050, Australia.
    30Department of Immunology, Westmead Hospital, University of Sydney, Westmead 2145, Australia.
    31Australian 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.
    32Pediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.
    33CeMM 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.
    34Pediatric Haematology and Oncology, University Hospital Essen, 45147 Essen, Germany.
    35Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06620 Ankara, Turkey.
    36University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.
    37University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.
    38Laboratory 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.
    39Laboratory 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.
    40Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
    41Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.
    42Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.
    43Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
    44Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
    45Laboratory 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.
    46Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
    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.


    © 2016 Ma et al.

    Publikations ID: 27401342
    Quelle: öffnen
     
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