STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function.
Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.
University of Bath, Bath BA2 7AY, England, UK Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
Robert P
RP
Wilson
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia St. Vincent's Clinical School and School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia.
Megan L
ML
Ives
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
Geetha
G
Rao
University of Bath, Bath BA2 7AY, England, UK Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
Anthony
A
Lau
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
Kathryn
K
Payne
Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan 739-8511.
Masao
M
Kobayashi
University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, England, UK.
Peter D
PD
Arkwright
Department of Paediatrics and Child Health, Royal Children's Hospital Brisbane, Brisbane, QLD 4006, Australia.
Jane
J
Peake
Department of Allergy and Immunology, Children's Hospital at Westmead, Westmead, Sydney, NSW 2145, Australia.
Melanie
M
Wong
Department of Clinical Immunology, Royal Prince Alfred Hospital, Camperdown, Sydney, NSW 2050, Australia.
Stephen
S
Adelstein
Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Parkville, VIC 3052, Australia.
Joanne M
JM
Smart
Department of Clinical Immunology, Royal Perth Hospital, Perth, WA 6000, Australia School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA 6009, Australia.
Martyn A
MA
French
Department of Immunology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, Sydney, NSW 2006, Australia.
David A
DA
Fulcher
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, French Institute of Health and Medical Research (INSERM) U1163 and Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital, 75015 Paris, France Imagine Institute, Paris Descartes University, 75015 Paris, France.
Capucine
C
Picard
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, French Institute of Health and Medical Research (INSERM) U1163 and Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital, 75015 Paris, France Imagine Institute, Paris Descartes University, 75015 Paris, France.
Jacinta
J
Bustamante
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, French Institute of Health and Medical Research (INSERM) U1163 and Pediatric Hematology and Immunology Unit, 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.
Stephanie
S
Boisson-Dupuis
St. Vincent's Clinical School and School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia.
Paul
P
Gray
Department of Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Medical Center, Hebrew University Medical Center, Jerusalem 91120, Israel.
Polina
P
Stepensky
Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, 79106 Freiburg, Germany.
Klaus
K
Warnatz
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.
Alexandra F
AF
Freeman
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences and Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia Department of Biochemistry and Molecular Biology, School of Biomedical Sciences and Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, UK.
Jamie
J
Rossjohn
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
James
J
McCluskey
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.
Steven M
SM
Holland
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, French Institute of Health and Medical Research (INSERM) U1163 and Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Laboratory of Human Genetics of Infectious Diseases, Necker Branch, French Institute of Health and Medical Research (INSERM) U1163 and Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France Imagine Institute, Paris Descartes University, 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.
Jean-Laurent
JL
Casanova
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892.
Gulbu
G
Uzel
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia St. Vincent's Clinical School and School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia.
Cindy S
CS
Ma
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia St. Vincent's Clinical School and School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia e.deenick@garvan.org.au s.tangye@garvan.org.au.
Stuart G
SG
Tangye
Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia St. Vincent's Clinical School and School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia e.deenick@garvan.org.au s.tangye@garvan.org.au.
Elissa K
EK
Deenick
D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008214:Lymphocytes / Q000166:cytology; D009154:Mutation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098546:Interleukin-21
D016207:Cytokines; C508438:IL12RB1 protein, human; C515500:IL23R protein, human; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000098546:Interleukin-21