期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 213, 期 8, 页码 1589-1608出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151467
关键词
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资金
- National Health and Medical Research Council (NHM RC) of Australia [596813, 1016953, 1066694, 1027400, 1004632]
- German Federal Ministry of Education and Research (BMBF) [01EO1303]
- Rockefeller University Center for 541 Clinical and Translational science [5UL1RR024143]
- NHMRC of Australia [1042925]
- Fulbright Commission
- [1008820]
- The Sir Jules Thorn Charitable Trust [12JTA] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [16H05355, 16K15529, 16H05356, 16K15528] Funding Source: KAKEN
- National Health and Medical Research Council of Australia [1066694] Funding Source: NHMRC
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. IL12R beta 1/TYK2 and IFN-gamma R/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. IL12R beta 1/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.
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