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

• DOI: 10.1084/jem.20141992
• Publication Date: 2015-05-05T01:32:49Z
• Authors: Robert P. Wilson; Megan L. Ives; Geetha Rao; Anthony Lau; Kathryn Payne; Masao Kobayashi; Peter D. Arkwright; Jane Peake; Melanie Wong; Stephen Adelstein; Joanne M. Smart; Martyn A. French; David A. Fulcher; Capucine Picard; Jacinta Bustamante; Stephanie Boisson...; Paul Gray; Polina Stepensky; Klaus Warnatz; Alexandra F. Freeman; Jamie Rossjohn; James McCluskey; Steven M. Holland; Jean-Laurent Casa...; Gulbu Uzel; Cindy S. Ma; Stuart G. Tangye; Elissa K. Deenick
• Keywords: STAT3 Transcription Factor; 570; 610; Cell Separation; Interleukin-23; Polymorphism, Single Nucleotide; Mait Cells; Interferon-gamma; 03 medical and health sciences; Clinical-Features; 0302 clinical medicine; Effector Functions; Humans; Dominant; Lymphocytes; Interleukins; Interleukin-17; Brief Definitive Report; Receptors, Interleukin-12; Receptors, Antigen, T-Cell, gamma-delta; Receptors, Interleukin; Nuclear Receptor Subfamily 1, Group F, Member 3; Flow Cytometry; Killer Cells, Natural; Differentiation; Mutation; Leukocytes, Mononuclear; Deficiency; Cytokines; Hyper-Ige Syndrome; Receptors, Interleukin-21; Ror-Gamma-T; Mutations; Receptor; Signal Transduction

Unconventional T cells such as γδ cells, natural killer (NKT cells) and mucosal-associated invariant (MAIT are a major component of the immune system; however, cytokine signaling pathways that control their development function in humans unknown. Primary immunodeficiencies caused by single gene mutations provide unique opportunity to investigate role specific molecules regulating human lymphocyte function. We found individuals with loss-of-function STAT3 had reduced numbers peripheral blood MAIT NKT but not cells. Analysis mosaic revealed this effect was cell intrinsic. Surprisingly, residual STAT3-deficient expressed normal levels transcription factor RORγt. Despite this, they displayed deficiency secretion IL-17A IL-17F, were able secrete cytokines IFNγ TNF. The patients mirrored IL12RB1 IL21R, respectively. Thus, these results reveal for first time essential downstream IL-23R IL-21R controlling numbers.