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J Exp Med. 2016 Jul 25;213(8):1589-608. doi: 10.1084/jem.20151467. Epub 2016 Jul 11.

Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.

Author information

1
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.
2
Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
3
Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.
4
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.
5
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.
6
Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.
7
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
8
Sydney Medical School, University of Sydney, Sydney 2006, Australia Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Camperdown 2050, Australia.
9
Department of Pediatric Immunology, Uludag University Medical Faculty, 16059 Görükle, Bursa, Turkey.
10
Genetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco.
11
Division of Molecular Medicine, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.
12
Clinical Immunology Unit, Department of Pediatrics, CHU Ibn Rochd, Casablanca, 20100, Morocco.
13
Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.
14
University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, England, UK.
15
Department of Clinical Immunology, Royal Perth Hospital, Perth 6009, Australia School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, Australia.
16
Starship Children's Hospital, Auckland 1023, New Zealand.
17
Children's Hospital at Westmead, Westmead 2145, Australia.
18
Sydney Medical School, University of Sydney, Sydney 2006, Australia Clinical Immunology, Royal Prince Alfred Hospital, Camperdown 2050, Australia.
19
Department of Immunology, Westmead Hospital, University of Sydney, Westmead 2145, Australia.
20
Australian 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.
21
Pediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.
22
CeMM 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.
23
Pediatric Haematology and Oncology, University Hospital Essen, 45147 Essen, Germany.
24
Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06620 Ankara, Turkey.
25
University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.
26
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.
27
Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.
28
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
29
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.

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.

PMID:
27401342
PMCID:
PMC4986526
DOI:
10.1084/jem.20151467
[Indexed for MEDLINE]
Free PMC Article

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