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

Robert P Wilson, Megan L Ives, Geetha Rao, Anthony Lau, Kathryn Payne, Masao Kobayashi, Peter Arkwright, Jane Peake, Melanie Wong, Stephen Adelstein, Joanne M Smart, Martyn A French, David A Fulcher, Capucine Picard, Jacinta Bustamante, Stephanie Boisson-Dupuis, Paul W Gray, Polina Y Stepensky, Klaus Warnatz, Alexandra F FreemanJamie Rossjohn, James McCluskey, Steven M Holland, Jean-Laurent Casanova, Gulbu Uzel, Cindy S Ma, Stuart G Tangye, Elissa K Deenick

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Unconventional T cells such as gammadelta 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 gammadelta 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 RORgammat. 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 IFNgamma 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.
Original languageEnglish
Pages (from-to)855 - 864
Number of pages10
JournalJournal of Experimental Medicine
Issue number6
Publication statusPublished - 2015

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