Cross-talk between T cell receptor and cytokine signaling is mediated by Itk: implications for the balance between Th17 and regulatory T cells (P1141)

Abstract

Abstract A proper balance between Th17 and T regulatory cells (Tregs) is critical for the generation of immune protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk influences the balance between Th17 and T regulatory cells by regulating crosstalk between T Cell Receptor (TCR) and cytokine signaling. Under both Th17 and Tregs differentiation conditions, Itk-/- CD4 T cells develop higher percentages of functional Foxp3+ cells, associated with increased responsiveness to IL-2. Itk-deficient CD4 cells show reduced TCR-induced phosphorylation of mTOR targets, including ribosomal S6 and AKT, accompanied by changes in metabolic signatures that are affected by mTOR pathways. Surprisingly, iTreg Itk-/- cells also show reduced IL-2-induced mTOR pathways, despite increased STAT5 phosphorylation. We find that TCR stimulation in WT CD4+ T cells leads to a dose-dependent repression of expression of Pten; however, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and PI3K/mTOR pathways and increasing Foxp3 expression. Functional studies show that naïve Itk-/- CD4 T cells also preferentially develop into Tregs in an in vivo colitis model. Furthermore Itk-deficient Tregs are capable to inhibit the development of colitis demonstrating that Treg function is independent of Itk. Our results suggest that Itk is a potential target for altering the balance between Th17 and Treg cells.