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ID 115511
Title Alternative
Regulation of human CD4+ T cell differentiation
Author
Ma, Cindy S. Garvan Institute of Medical Research|St Vincent’s Clinical School
Wong, Natalie Garvan Institute of Medical Research
Rao, Geetha Garvan Institute of Medical Research
Nguyen, Akira Garvan Institute of Medical Research|St Vincent’s Clinical School
Avery, Danielle T. Garvan Institute of Medical Research
Payne, Kathryn Garvan Institute of Medical Research
Torpy, James Garvan Institute of Medical Research
O’Young, Patrick Garvan Institute of Medical Research|St Vincent’s Clinical School
Deenick, Elissa Garvan Institute of Medical Research|St Vincent’s Clinical School
Bustamante, Jacinta INSERM|Necker Hospital for Sick Children|The Rockefeller University|Paris Descartes University
Puel, Anne INSERM|Necker Hospital for Sick Children|Paris Descartes University
Okada, Satoshi Hiroshima University
Kobayashi, Masao Hiroshima University
Martinez-Barricarte, Ruben The Rockefeller University
Elliott, Michael University of Sydney|Royal Prince Alfred Hospital
Kilic, Sara Sebnem Uludag University
Baghdadi, Jamila El Military Hospital Mohamed V
Bousfiha, Aziz CHU Ibn Rochd
Robertson, Nic Newcastle University
Hambleton, Sophie Newcastle University
Arkwright, Peter D. University of Manchester
French, Martyn Royal Perth Hospital|University of Western Australia
Blincoe, Annaliesse K. Starship Children's Hospital
Hsu, Peter Children’s Hospital at Westmead
Campbell, Dianne E. Children’s Hospital at Westmead
Stormon, Michael O. Children’s Hospital at Westmead
Wong, Melanie Children’s Hospital at Westmead
Adelstein, Stephen University of Sydney|Royal Prince Alfred Hospital
Fulcher, David A. University of Sydney
Cook, Matthew C. Australian National University|The Canberra Hospital|Hebrew University
Stepensky, Polina Hebrew University
Boztug, Kaan Medical University of Vienna
Beier, Rita University Hospital Essen
Ikincioğullari, Aydan Ankara University
Ziegler, John B. University of New South Wales
Gray, Paul University of New South Wales
Picard, Capucine INSERM|Necker Hospital for Sick Children|The Rockefeller University|Paris Descartes University
Boisson-Dupuis, Stéphanie INSERM|The Rockefeller University|Paris Descartes University
Phan, Tri Giang Garvan Institute of Medical Research|St Vincent’s Clinical School
Grimbacher, Bodo University of Freiburg
Warnatz, Klaus University of Freiburg
Holland, Steven M. National Institutes of Health
Uzel, Gulbu National Institutes of Health
Casanova, Jean-Laurent INSERM|Necker Hospital for Sick Children|The Rockefeller University|Howard Hughes Medical Institute|Paris Descartes University
Tangye, Stuart G. Garvan Institute of Medical Research|St Vincent’s Clinical School
Content Type
Journal Article
Description
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.
Journal Title
Journal of Experimental Medicine
ISSN
00221007
15409538
NCID
AA00697559
AA12119243
Publisher
Rockefeller University Press
Volume
213
Issue
8
Start Page
1589
End Page
1608
Published Date
2016-07-11
Rights
© 2016 Ma et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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DOI (Published Version)
URL ( Publisher's Version )
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language
eng
TextVersion
Publisher
departments
Institute of Advanced Medical Sciences