Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.
Identifieur interne : 001C33 ( PubMed/Corpus ); précédent : 001C32; suivant : 001C34Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.
Auteurs : Cindy S. Ma ; Natalie Wong ; Geetha Rao ; Akira Nguyen ; Danielle T. Avery ; Kathryn Payne ; James Torpy ; Patrick O'Young ; Elissa Deenick ; Jacinta Bustamante ; Anne Puel ; Satoshi Okada ; Masao Kobayashi ; Ruben Martinez-Barricarte ; Michael Elliott ; Sara Sebnem Kilic ; Jamila El Baghdadi ; Yoshiyuki Minegishi ; Aziz Bousfiha ; Nic Robertson ; Sophie Hambleton ; Peter D. Arkwright ; Martyn French ; Annaliesse K. Blincoe ; Peter Hsu ; Dianne E. Campbell ; Michael O. Stormon ; Melanie Wong ; Stephen Adelstein ; David A. Fulcher ; Matthew C. Cook ; Polina Stepensky ; Kaan Boztug ; Rita Beier ; Aydan Ikincio Ullari ; John B. Ziegler ; Paul Gray ; Capucine Picard ; Stéphanie Boisson-Dupuis ; Tri Giang Phan ; Bodo Grimbacher ; Klaus Warnatz ; Steven M. Holland ; Gulbu Uzel ; Jean-Laurent Casanova ; Stuart G. TangyeSource :
- The Journal of experimental medicine [ 1540-9538 ] ; 2016.
English descriptors
- KwdEn :
- Antigens, Differentiation (genetics), Antigens, Differentiation (immunology), Cell Differentiation (genetics), Cell Differentiation (immunology), Female, Humans, Interleukin-10 (genetics), Interleukin-10 (immunology), Male, Mutation, STAT1 Transcription Factor (genetics), STAT1 Transcription Factor (immunology), STAT3 Transcription Factor (genetics), STAT3 Transcription Factor (immunology), Th1 Cells (cytology), Th1 Cells (immunology), Th17 Cells (cytology), Th17 Cells (immunology), Th2 Cells (immunology).
- MESH :
- chemical , genetics : Antigens, Differentiation, Interleukin-10, STAT1 Transcription Factor, STAT3 Transcription Factor.
- chemical , immunology : Antigens, Differentiation, Interleukin-10, STAT1 Transcription Factor, STAT3 Transcription Factor.
- cytology : Th1 Cells, Th17 Cells.
- genetics : Cell Differentiation.
- immunology : Cell Differentiation, Th1 Cells, Th17 Cells, Th2 Cells.
- Female, Humans, Male, Mutation.
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.
DOI: 10.1084/jem.20151467
PubMed: 27401342
Links to Exploration step
pubmed:27401342Le document en format XML
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Ma</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Wong, Natalie" sort="Wong, Natalie" uniqKey="Wong N" first="Natalie" last="Wong">Natalie Wong</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Rao, Geetha" sort="Rao, Geetha" uniqKey="Rao G" first="Geetha" last="Rao">Geetha Rao</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Nguyen, Akira" sort="Nguyen, Akira" uniqKey="Nguyen A" first="Akira" last="Nguyen">Akira Nguyen</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Avery, Danielle T" sort="Avery, Danielle T" uniqKey="Avery D" first="Danielle T" last="Avery">Danielle T. Avery</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Payne, Kathryn" sort="Payne, Kathryn" uniqKey="Payne K" first="Kathryn" last="Payne">Kathryn Payne</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Torpy, James" sort="Torpy, James" uniqKey="Torpy J" first="James" last="Torpy">James Torpy</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="O Young, Patrick" sort="O Young, Patrick" uniqKey="O Young P" first="Patrick" last="O'Young">Patrick O'Young</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Deenick, Elissa" sort="Deenick, Elissa" uniqKey="Deenick E" first="Elissa" last="Deenick">Elissa Deenick</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Bustamante, Jacinta" sort="Bustamante, Jacinta" uniqKey="Bustamante J" first="Jacinta" last="Bustamante">Jacinta Bustamante</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Okada, Satoshi" sort="Okada, Satoshi" uniqKey="Okada S" first="Satoshi" last="Okada">Satoshi Okada</name><affiliation><nlm:affiliation>Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Kobayashi, Masao" sort="Kobayashi, Masao" uniqKey="Kobayashi M" first="Masao" last="Kobayashi">Masao Kobayashi</name><affiliation><nlm:affiliation>Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Martinez Barricarte, Ruben" sort="Martinez Barricarte, Ruben" uniqKey="Martinez Barricarte R" first="Ruben" last="Martinez-Barricarte">Ruben Martinez-Barricarte</name><affiliation><nlm:affiliation>St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.</nlm:affiliation></affiliation></author><author><name sortKey="Elliott, Michael" sort="Elliott, Michael" uniqKey="Elliott M" first="Michael" last="Elliott">Michael Elliott</name><affiliation><nlm:affiliation>Sydney Medical School, University of Sydney, Sydney 2006, Australia Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Camperdown 2050, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Sebnem Kilic, Sara" sort="Sebnem Kilic, Sara" uniqKey="Sebnem Kilic S" first="Sara" last="Sebnem Kilic">Sara Sebnem Kilic</name><affiliation><nlm:affiliation>Department of Pediatric Immunology, Uludag University Medical Faculty, 16059 Görükle, Bursa, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="El Baghdadi, Jamila" sort="El Baghdadi, Jamila" uniqKey="El Baghdadi J" first="Jamila" last="El Baghdadi">Jamila El Baghdadi</name><affiliation><nlm:affiliation>Genetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco.</nlm:affiliation></affiliation></author><author><name sortKey="Minegishi, Yoshiyuki" sort="Minegishi, Yoshiyuki" uniqKey="Minegishi Y" first="Yoshiyuki" last="Minegishi">Yoshiyuki Minegishi</name><affiliation><nlm:affiliation>Division of Molecular Medicine, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Bousfiha, Aziz" sort="Bousfiha, Aziz" uniqKey="Bousfiha A" first="Aziz" last="Bousfiha">Aziz Bousfiha</name><affiliation><nlm:affiliation>Clinical Immunology Unit, Department of Pediatrics, CHU Ibn Rochd, Casablanca, 20100, Morocco.</nlm:affiliation></affiliation></author><author><name sortKey="Robertson, Nic" sort="Robertson, Nic" uniqKey="Robertson N" first="Nic" last="Robertson">Nic Robertson</name><affiliation><nlm:affiliation>Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Hambleton, Sophie" sort="Hambleton, Sophie" uniqKey="Hambleton S" first="Sophie" last="Hambleton">Sophie Hambleton</name><affiliation><nlm:affiliation>Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Arkwright, Peter D" sort="Arkwright, Peter D" uniqKey="Arkwright P" first="Peter D" last="Arkwright">Peter D. Arkwright</name><affiliation><nlm:affiliation>University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, England, UK.</nlm:affiliation></affiliation></author><author><name sortKey="French, Martyn" sort="French, Martyn" uniqKey="French M" first="Martyn" last="French">Martyn French</name><affiliation><nlm:affiliation>Department of Clinical Immunology, Royal Perth Hospital, Perth 6009, Australia School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Blincoe, Annaliesse K" sort="Blincoe, Annaliesse K" uniqKey="Blincoe A" first="Annaliesse K" last="Blincoe">Annaliesse K. Blincoe</name><affiliation><nlm:affiliation>Starship Children's Hospital, Auckland 1023, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Hsu, Peter" sort="Hsu, Peter" uniqKey="Hsu P" first="Peter" last="Hsu">Peter Hsu</name><affiliation><nlm:affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Campbell, Dianne E" sort="Campbell, Dianne E" uniqKey="Campbell D" first="Dianne E" last="Campbell">Dianne E. Campbell</name><affiliation><nlm:affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Stormon, Michael O" sort="Stormon, Michael O" uniqKey="Stormon M" first="Michael O" last="Stormon">Michael O. Stormon</name><affiliation><nlm:affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Wong, Melanie" sort="Wong, Melanie" uniqKey="Wong M" first="Melanie" last="Wong">Melanie Wong</name><affiliation><nlm:affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Adelstein, Stephen" sort="Adelstein, Stephen" uniqKey="Adelstein S" first="Stephen" last="Adelstein">Stephen Adelstein</name><affiliation><nlm:affiliation>Sydney Medical School, University of Sydney, Sydney 2006, Australia Clinical Immunology, Royal Prince Alfred Hospital, Camperdown 2050, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Fulcher, David A" sort="Fulcher, David A" uniqKey="Fulcher D" first="David A" last="Fulcher">David A. Fulcher</name><affiliation><nlm:affiliation>Department of Immunology, Westmead Hospital, University of Sydney, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Cook, Matthew C" sort="Cook, Matthew C" uniqKey="Cook M" first="Matthew C" last="Cook">Matthew C. Cook</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Stepensky, Polina" sort="Stepensky, Polina" uniqKey="Stepensky P" first="Polina" last="Stepensky">Polina Stepensky</name><affiliation><nlm:affiliation>Pediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.</nlm:affiliation></affiliation></author><author><name sortKey="Boztug, Kaan" sort="Boztug, Kaan" uniqKey="Boztug K" first="Kaan" last="Boztug">Kaan Boztug</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Beier, Rita" sort="Beier, Rita" uniqKey="Beier R" first="Rita" last="Beier">Rita Beier</name><affiliation><nlm:affiliation>Pediatric Haematology and Oncology, University Hospital Essen, 45147 Essen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Ikincio Ullari, Aydan" sort="Ikincio Ullari, Aydan" uniqKey="Ikincio Ullari A" first="Aydan" last="Ikincio Ullari">Aydan Ikincio Ullari</name><affiliation><nlm:affiliation>Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06620 Ankara, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Ziegler, John B" sort="Ziegler, John B" uniqKey="Ziegler J" first="John B" last="Ziegler">John B. Ziegler</name><affiliation><nlm:affiliation>University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Gray, Paul" sort="Gray, Paul" uniqKey="Gray P" first="Paul" last="Gray">Paul Gray</name><affiliation><nlm:affiliation>University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Boisson Dupuis, Stephanie" sort="Boisson Dupuis, Stephanie" uniqKey="Boisson Dupuis S" first="Stéphanie" last="Boisson-Dupuis">Stéphanie Boisson-Dupuis</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Phan, Tri Giang" sort="Phan, Tri Giang" uniqKey="Phan T" first="Tri Giang" last="Phan">Tri Giang Phan</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Grimbacher, Bodo" sort="Grimbacher, Bodo" uniqKey="Grimbacher B" first="Bodo" last="Grimbacher">Bodo Grimbacher</name><affiliation><nlm:affiliation>Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Warnatz, Klaus" sort="Warnatz, Klaus" uniqKey="Warnatz K" first="Klaus" last="Warnatz">Klaus Warnatz</name><affiliation><nlm:affiliation>Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M" last="Holland">Steven M. Holland</name><affiliation><nlm:affiliation>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.</nlm:affiliation></affiliation></author><author><name sortKey="Uzel, Gulbu" sort="Uzel, Gulbu" uniqKey="Uzel G" first="Gulbu" last="Uzel">Gulbu Uzel</name><affiliation><nlm:affiliation>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.</nlm:affiliation></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Tangye, Stuart G" sort="Tangye, Stuart G" uniqKey="Tangye S" first="Stuart G" last="Tangye">Stuart G. Tangye</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27401342</idno><idno type="pmid">27401342</idno><idno type="doi">10.1084/jem.20151467</idno><idno type="wicri:Area/PubMed/Corpus">001C33</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001C33</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.</title><author><name sortKey="Ma, Cindy S" sort="Ma, Cindy S" uniqKey="Ma C" first="Cindy S" last="Ma">Cindy S. Ma</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Wong, Natalie" sort="Wong, Natalie" uniqKey="Wong N" first="Natalie" last="Wong">Natalie Wong</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Rao, Geetha" sort="Rao, Geetha" uniqKey="Rao G" first="Geetha" last="Rao">Geetha Rao</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Nguyen, Akira" sort="Nguyen, Akira" uniqKey="Nguyen A" first="Akira" last="Nguyen">Akira Nguyen</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Avery, Danielle T" sort="Avery, Danielle T" uniqKey="Avery D" first="Danielle T" last="Avery">Danielle T. Avery</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Payne, Kathryn" sort="Payne, Kathryn" uniqKey="Payne K" first="Kathryn" last="Payne">Kathryn Payne</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Torpy, James" sort="Torpy, James" uniqKey="Torpy J" first="James" last="Torpy">James Torpy</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="O Young, Patrick" sort="O Young, Patrick" uniqKey="O Young P" first="Patrick" last="O'Young">Patrick O'Young</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Deenick, Elissa" sort="Deenick, Elissa" uniqKey="Deenick E" first="Elissa" last="Deenick">Elissa Deenick</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Bustamante, Jacinta" sort="Bustamante, Jacinta" uniqKey="Bustamante J" first="Jacinta" last="Bustamante">Jacinta Bustamante</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Puel, Anne" sort="Puel, Anne" uniqKey="Puel A" first="Anne" last="Puel">Anne Puel</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Okada, Satoshi" sort="Okada, Satoshi" uniqKey="Okada S" first="Satoshi" last="Okada">Satoshi Okada</name><affiliation><nlm:affiliation>Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Kobayashi, Masao" sort="Kobayashi, Masao" uniqKey="Kobayashi M" first="Masao" last="Kobayashi">Masao Kobayashi</name><affiliation><nlm:affiliation>Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Martinez Barricarte, Ruben" sort="Martinez Barricarte, Ruben" uniqKey="Martinez Barricarte R" first="Ruben" last="Martinez-Barricarte">Ruben Martinez-Barricarte</name><affiliation><nlm:affiliation>St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.</nlm:affiliation></affiliation></author><author><name sortKey="Elliott, Michael" sort="Elliott, Michael" uniqKey="Elliott M" first="Michael" last="Elliott">Michael Elliott</name><affiliation><nlm:affiliation>Sydney Medical School, University of Sydney, Sydney 2006, Australia Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Camperdown 2050, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Sebnem Kilic, Sara" sort="Sebnem Kilic, Sara" uniqKey="Sebnem Kilic S" first="Sara" last="Sebnem Kilic">Sara Sebnem Kilic</name><affiliation><nlm:affiliation>Department of Pediatric Immunology, Uludag University Medical Faculty, 16059 Görükle, Bursa, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="El Baghdadi, Jamila" sort="El Baghdadi, Jamila" uniqKey="El Baghdadi J" first="Jamila" last="El Baghdadi">Jamila El Baghdadi</name><affiliation><nlm:affiliation>Genetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco.</nlm:affiliation></affiliation></author><author><name sortKey="Minegishi, Yoshiyuki" sort="Minegishi, Yoshiyuki" uniqKey="Minegishi Y" first="Yoshiyuki" last="Minegishi">Yoshiyuki Minegishi</name><affiliation><nlm:affiliation>Division of Molecular Medicine, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Bousfiha, Aziz" sort="Bousfiha, Aziz" uniqKey="Bousfiha A" first="Aziz" last="Bousfiha">Aziz Bousfiha</name><affiliation><nlm:affiliation>Clinical Immunology Unit, Department of Pediatrics, CHU Ibn Rochd, Casablanca, 20100, Morocco.</nlm:affiliation></affiliation></author><author><name sortKey="Robertson, Nic" sort="Robertson, Nic" uniqKey="Robertson N" first="Nic" last="Robertson">Nic Robertson</name><affiliation><nlm:affiliation>Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Hambleton, Sophie" sort="Hambleton, Sophie" uniqKey="Hambleton S" first="Sophie" last="Hambleton">Sophie Hambleton</name><affiliation><nlm:affiliation>Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.</nlm:affiliation></affiliation></author><author><name sortKey="Arkwright, Peter D" sort="Arkwright, Peter D" uniqKey="Arkwright P" first="Peter D" last="Arkwright">Peter D. Arkwright</name><affiliation><nlm:affiliation>University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, England, UK.</nlm:affiliation></affiliation></author><author><name sortKey="French, Martyn" sort="French, Martyn" uniqKey="French M" first="Martyn" last="French">Martyn French</name><affiliation><nlm:affiliation>Department of Clinical Immunology, Royal Perth Hospital, Perth 6009, Australia School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Blincoe, Annaliesse K" sort="Blincoe, Annaliesse K" uniqKey="Blincoe A" first="Annaliesse K" last="Blincoe">Annaliesse K. Blincoe</name><affiliation><nlm:affiliation>Starship Children's Hospital, Auckland 1023, New Zealand.</nlm:affiliation></affiliation></author><author><name sortKey="Hsu, Peter" sort="Hsu, Peter" uniqKey="Hsu P" first="Peter" last="Hsu">Peter Hsu</name><affiliation><nlm:affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Campbell, Dianne E" sort="Campbell, Dianne E" uniqKey="Campbell D" first="Dianne E" last="Campbell">Dianne E. Campbell</name><affiliation><nlm:affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Stormon, Michael O" sort="Stormon, Michael O" uniqKey="Stormon M" first="Michael O" last="Stormon">Michael O. Stormon</name><affiliation><nlm:affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Wong, Melanie" sort="Wong, Melanie" uniqKey="Wong M" first="Melanie" last="Wong">Melanie Wong</name><affiliation><nlm:affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Adelstein, Stephen" sort="Adelstein, Stephen" uniqKey="Adelstein S" first="Stephen" last="Adelstein">Stephen Adelstein</name><affiliation><nlm:affiliation>Sydney Medical School, University of Sydney, Sydney 2006, Australia Clinical Immunology, Royal Prince Alfred Hospital, Camperdown 2050, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Fulcher, David A" sort="Fulcher, David A" uniqKey="Fulcher D" first="David A" last="Fulcher">David A. Fulcher</name><affiliation><nlm:affiliation>Department of Immunology, Westmead Hospital, University of Sydney, Westmead 2145, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Cook, Matthew C" sort="Cook, Matthew C" uniqKey="Cook M" first="Matthew C" last="Cook">Matthew C. Cook</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Stepensky, Polina" sort="Stepensky, Polina" uniqKey="Stepensky P" first="Polina" last="Stepensky">Polina Stepensky</name><affiliation><nlm:affiliation>Pediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.</nlm:affiliation></affiliation></author><author><name sortKey="Boztug, Kaan" sort="Boztug, Kaan" uniqKey="Boztug K" first="Kaan" last="Boztug">Kaan Boztug</name><affiliation><nlm:affiliation>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.</nlm:affiliation></affiliation></author><author><name sortKey="Beier, Rita" sort="Beier, Rita" uniqKey="Beier R" first="Rita" last="Beier">Rita Beier</name><affiliation><nlm:affiliation>Pediatric Haematology and Oncology, University Hospital Essen, 45147 Essen, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Ikincio Ullari, Aydan" sort="Ikincio Ullari, Aydan" uniqKey="Ikincio Ullari A" first="Aydan" last="Ikincio Ullari">Aydan Ikincio Ullari</name><affiliation><nlm:affiliation>Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06620 Ankara, Turkey.</nlm:affiliation></affiliation></author><author><name sortKey="Ziegler, John B" sort="Ziegler, John B" uniqKey="Ziegler J" first="John B" last="Ziegler">John B. Ziegler</name><affiliation><nlm:affiliation>University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Gray, Paul" sort="Gray, Paul" uniqKey="Gray P" first="Paul" last="Gray">Paul Gray</name><affiliation><nlm:affiliation>University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Picard, Capucine" sort="Picard, Capucine" uniqKey="Picard C" first="Capucine" last="Picard">Capucine Picard</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Boisson Dupuis, Stephanie" sort="Boisson Dupuis, Stephanie" uniqKey="Boisson Dupuis S" first="Stéphanie" last="Boisson-Dupuis">Stéphanie Boisson-Dupuis</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Phan, Tri Giang" sort="Phan, Tri Giang" uniqKey="Phan T" first="Tri Giang" last="Phan">Tri Giang Phan</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Grimbacher, Bodo" sort="Grimbacher, Bodo" uniqKey="Grimbacher B" first="Bodo" last="Grimbacher">Bodo Grimbacher</name><affiliation><nlm:affiliation>Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Warnatz, Klaus" sort="Warnatz, Klaus" uniqKey="Warnatz K" first="Klaus" last="Warnatz">Klaus Warnatz</name><affiliation><nlm:affiliation>Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79085 Freiburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M" last="Holland">Steven M. Holland</name><affiliation><nlm:affiliation>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.</nlm:affiliation></affiliation></author><author><name sortKey="Uzel, Gulbu" sort="Uzel, Gulbu" uniqKey="Uzel G" first="Gulbu" last="Uzel">Gulbu Uzel</name><affiliation><nlm:affiliation>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.</nlm:affiliation></affiliation></author><author><name sortKey="Casanova, Jean Laurent" sort="Casanova, Jean Laurent" uniqKey="Casanova J" first="Jean-Laurent" last="Casanova">Jean-Laurent Casanova</name><affiliation><nlm: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.</nlm:affiliation></affiliation></author><author><name sortKey="Tangye, Stuart G" sort="Tangye, Stuart G" uniqKey="Tangye S" first="Stuart G" last="Tangye">Stuart G. Tangye</name><affiliation><nlm:affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</nlm:affiliation></affiliation></author></analytic><series><title level="j">The Journal of experimental medicine</title><idno type="eISSN">1540-9538</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antigens, Differentiation (genetics)</term><term>Antigens, Differentiation (immunology)</term><term>Cell Differentiation (genetics)</term><term>Cell Differentiation (immunology)</term><term>Female</term><term>Humans</term><term>Interleukin-10 (genetics)</term><term>Interleukin-10 (immunology)</term><term>Male</term><term>Mutation</term><term>STAT1 Transcription Factor (genetics)</term><term>STAT1 Transcription Factor (immunology)</term><term>STAT3 Transcription Factor (genetics)</term><term>STAT3 Transcription Factor (immunology)</term><term>Th1 Cells (cytology)</term><term>Th1 Cells (immunology)</term><term>Th17 Cells (cytology)</term><term>Th17 Cells (immunology)</term><term>Th2 Cells (immunology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Antigens, Differentiation</term><term>Interleukin-10</term><term>STAT1 Transcription Factor</term><term>STAT3 Transcription Factor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Antigens, Differentiation</term><term>Interleukin-10</term><term>STAT1 Transcription Factor</term><term>STAT3 Transcription Factor</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Th1 Cells</term><term>Th17 Cells</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cell Differentiation</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Cell Differentiation</term><term>Th1 Cells</term><term>Th17 Cells</term><term>Th2 Cells</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Female</term><term>Humans</term><term>Male</term><term>Mutation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27401342</PMID><DateCreated><Year>2016</Year><Month>07</Month><Day>26</Day></DateCreated><DateCompleted><Year>2017</Year><Month>07</Month><Day>27</Day></DateCompleted><DateRevised><Year>2017</Year><Month>07</Month><Day>27</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1540-9538</ISSN><JournalIssue CitedMedium="Internet"><Volume>213</Volume><Issue>8</Issue><PubDate><Year>2016</Year><Month>Jul</Month><Day>25</Day></PubDate></JournalIssue><Title>The Journal of experimental medicine</Title><ISOAbbreviation>J. Exp. Med.</ISOAbbreviation></Journal><ArticleTitle>Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.</ArticleTitle><Pagination><MedlinePgn>1589-608</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1084/jem.20151467</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>© 2016 Ma et al.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Ma</LastName><ForeName>Cindy S</ForeName><Initials>CS</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wong</LastName><ForeName>Natalie</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rao</LastName><ForeName>Geetha</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nguyen</LastName><ForeName>Akira</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Avery</LastName><ForeName>Danielle T</ForeName><Initials>DT</Initials><AffiliationInfo><Affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Payne</LastName><ForeName>Kathryn</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Torpy</LastName><ForeName>James</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>O'Young</LastName><ForeName>Patrick</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Deenick</LastName><ForeName>Elissa</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Immunology Division, Garvan Institute of Medical Research, Darlinghurst 2010, Australia St Vincent's Clinical School, Darlinghurst 2010, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bustamante</LastName><ForeName>Jacinta</ForeName><Initials>J</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Puel</LastName><ForeName>Anne</ForeName><Initials>A</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Okada</LastName><ForeName>Satoshi</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kobayashi</LastName><ForeName>Masao</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima 735-8911, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martinez-Barricarte</LastName><ForeName>Ruben</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Elliott</LastName><ForeName>Michael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Sydney Medical School, University of Sydney, Sydney 2006, Australia Chris O'Brien Lifehouse Cancer Centre, Royal Prince Alfred Hospital, Camperdown 2050, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sebnem Kilic</LastName><ForeName>Sara</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Pediatric Immunology, Uludag University Medical Faculty, 16059 Görükle, Bursa, Turkey.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>El Baghdadi</LastName><ForeName>Jamila</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Genetics Unit, Military Hospital Mohamed V, Hay Riad, 10100 Rabat, Morocco.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Minegishi</LastName><ForeName>Yoshiyuki</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>Division of Molecular Medicine, Institute for Genome Research, The University of Tokushima, Tokushima 770-8503, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bousfiha</LastName><ForeName>Aziz</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Clinical Immunology Unit, Department of Pediatrics, CHU Ibn Rochd, Casablanca, 20100, Morocco.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Robertson</LastName><ForeName>Nic</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hambleton</LastName><ForeName>Sophie</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Arkwright</LastName><ForeName>Peter D</ForeName><Initials>PD</Initials><AffiliationInfo><Affiliation>University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WL, England, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>French</LastName><ForeName>Martyn</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Clinical Immunology, Royal Perth Hospital, Perth 6009, Australia School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Blincoe</LastName><ForeName>Annaliesse K</ForeName><Initials>AK</Initials><AffiliationInfo><Affiliation>Starship Children's Hospital, Auckland 1023, New Zealand.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hsu</LastName><ForeName>Peter</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Campbell</LastName><ForeName>Dianne E</ForeName><Initials>DE</Initials><AffiliationInfo><Affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stormon</LastName><ForeName>Michael O</ForeName><Initials>MO</Initials><AffiliationInfo><Affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wong</LastName><ForeName>Melanie</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Children's Hospital at Westmead, Westmead 2145, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Adelstein</LastName><ForeName>Stephen</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Sydney Medical School, University of Sydney, Sydney 2006, Australia Clinical Immunology, Royal Prince Alfred Hospital, Camperdown 2050, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fulcher</LastName><ForeName>David A</ForeName><Initials>DA</Initials><AffiliationInfo><Affiliation>Department of Immunology, Westmead Hospital, University of Sydney, Westmead 2145, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cook</LastName><ForeName>Matthew C</ForeName><Initials>MC</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stepensky</LastName><ForeName>Polina</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Pediatric Hematology-Oncology and Bone Marrow Transplantation Hadassah, Hebrew University Medical Center, Jerusalem 91120, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Boztug</LastName><ForeName>Kaan</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Beier</LastName><ForeName>Rita</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Pediatric Haematology and Oncology, University Hospital Essen, 45147 Essen, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ikincioğullari</LastName><ForeName>Aydan</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Pediatric Immunology and Allergy, Ankara University Medical School, 06620 Ankara, Turkey.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ziegler</LastName><ForeName>John B</ForeName><Initials>JB</Initials><AffiliationInfo><Affiliation>University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gray</LastName><ForeName>Paul</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>University of New South Wales School of Women's and Children's Health, Randwick 2031, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Picard</LastName><ForeName>Capucine</ForeName><Initials>C</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Boisson-Dupuis</LastName><ForeName>Stéphanie</ForeName><Initials>S</Initials><AffiliationInfo><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 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Freiburg, 79085 Freiburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Holland</LastName><ForeName>Steven M</ForeName><Initials>SM</Initials><AffiliationInfo><Affiliation>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Uzel</LastName><ForeName>Gulbu</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Casanova</LastName><ForeName>Jean-Laurent</ForeName><Initials>JL</Initials><AffiliationInfo><Affiliation>Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163,75270 Paris, France Pediatric Hematology and Immunology Unit, Assistance 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