期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 212, 期 6, 页码 855-864出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20141992
关键词
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资金
- National Health and Medical Research Council (NHMRC) of Australia [1016953, 1066694, 1027400]
- Rockefeller University Center for 541 Clinical and Translational Science [5UL1RR024143]
- Career Development Fellowship [1008820]
- NHMRC of Australia [1042925]
- National Health and Medical Research Council of Australia [1066694] Funding Source: NHMRC
Unconventional T cells such as gamma delta 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 gamma delta 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 ROR gamma t. 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 IFN gamma 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.
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