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STAT3 is a critical cell intrinsic regulator of human unconventional T cell numbers and function

Abstract

Unconventional T cells such as ?? T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are a major component of the immune system, however, the signalling pathways that control their development and function remain unclear. Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immunodeficiency caused by heterozygous dominant negative mutations in STAT3 and characterised by recurrent infections with Candida albicans and Staphylococcus aureus. Here, we found that STAT3 deficiency caused a decrease in MAIT and NKT, but not ?? T, cell numbers in the blood. 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?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? and TNF?. Detailed analysis of cytokine receptor expression, STAT activation and individuals with loss of function mutations in IL12RB1 and IL21R revealed that IL-23R/STAT3 signalling was required for maintenance of MAIT cells while IL-21R/STAT3 controlled NKT cell numbers.

Type Journal
Authors Wilson RP, Ives ML, Rao G, Lau A, Payne K, Kobayashi M, Arkwright PD, Peake J, Wong M, Adelstein S, Smart JM, French MA, Fulcher DA, Picard C, Bustamante J, Boisson-Dupuis S, Gray P, Stepensky P, Warnatz K, Freeman AF, Rossjohn J, McCluskey J, Holland SM, Casanova JL, Uze G, Ma C, Tangye SG and Deenick E.
Publisher Name J EXP MED
Published Date 2015-05-04 00:00:00
Published Volume 212
Published Pages 855-864
Status Published in-print