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

Abstract

Th17 cells play major roles in autoimmunity and bacterial infections, yet how T cell receptor (TCR) signaling affects Th17 differentiation is relatively unknown. We demonstrate that CD4+ T cells deficient in Itk, a tyrosine kinase required for full TCR-induced activation of PLC-γ, exhibit decreased IL-17A expression, yet relatively normal expression of RORγT, RORα and IL-17F. IL-17A expression was rescued by pharmacologically-induced Ca2+ influx or expression of activated NFATc1. Conversely, decreased TCR stimulation or FK506 treatment preferentially reduced expression of IL-17A. The promoter of IL-17A but not IL-17F has conserved NFAT binding sites that bind NFATc1 in WT, but not Itk-deficient cells, even though both promoters exhibit epigenetic modifications consistent with open chromatin. Finally, defective IL-17A expression and differential regulation of IL-17A and IL-17F were observed in vivo in Itk−/− mice in an allergic asthma model. Our results suggest that Itk specifically couples TCR signaling strength to IL-17A expression through NFATc1.

Trithorax complex component Menin controls differentiation and maintenance of T helper 17 cells

“…1B). The strength of T-cell receptor (TCR) signaling is also known to regulate IL-17 production (28,29). We therefore investigated whether alteration of TCR stimulation could affect the reduced generation of IL-17-producing cells in Menin −/− T-cell cultures.…”

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

“…Deletion of RLK alone has few functional consequences, but deletion of RLK in combination with ITK appears to be important in Th1 cells, where it is preferentially expressed. In addition, the deletion of ITK and RLK has a marked effect on Th17 differentiation and IL-17 production (13). In some settings, it appears that ITK and RLK are redundant signaling molecules because overexpression of RLK in ITK Ϫ/Ϫ mice rescues the Th2 response in a model of asthma (14).…”

1,25-Dihydroxyvitamin D3Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A

“…In IL-17A knockout (KO) mice, EAE is markedly suppressed, indicating that IL-17 contributes to the development of EAE (33). Although it has been reported that the transcription factors nuclear factor for activated T cells (NFAT), retinoid orphan nuclear receptor ␥t (ROR␥t), and Runt-related transcription factor 1 (Runx1) are important for the T cell receptor (TCR)-mediated transcriptional regulation of IL-17A (24,29,38,74), knowledge of the factors involved in the cellular and molecular regulation of IL-17A remains limited.…”