Differential Expression of Interleukin-17A and -17F is Coupled to T Cell Receptor Signaling Via Inducible T Cell Kinase

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2009 Oct 13

PMID 19818650

Citations 116

Authors

Julio Gomez-Rodriguez

Nisebita Sahu

Robin Handon

Todd S Davidson

Stacie M Anderson

Martha R Kirby

Avery August

Pamela L Schwartzberg

Affiliations

Soon will be listed here.

Abstract

T helper 17 (Th17) cells play major roles in autoimmunity and bacterial infections, yet how T cell receptor (TCR) signaling affects Th17 cell differentiation is relatively unknown. We demonstrate that CD4(+) T cells lacking Itk, a tyrosine kinase required for full TCR-induced phospholipase C-gamma (PLC-gamma1) activation, exhibit decreased interleukin-17A (IL-17A) expression in vitro and in vivo, despite relatively normal expression of retinoic acid receptor-related orphan receptor-gammaT (ROR-gammaT) and IL-17F. IL-17A expression was rescued by pharmacologically induced Ca(2+) influx or constitutively activated nuclear factor of activated T cells (NFAT). Conversely, decreased TCR stimulation or calcineurin inhibition preferentially reduced IL-17A expression. We further found that the promoter of Il17a but not Il17f has a conserved NFAT binding site that bound NFATc1 in wild-type but not Itk-deficient cells, even though both exhibited open chromatin conformations. Finally, Itk(-/-) mice also showed differential regulation of IL-17A and IL-17F in vivo. Our results suggest that Itk specifically couples TCR signaling to Il17a expression and the differential regulation of Th17 cell cytokines through NFATc1.

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