Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells

作者：Gomez Rodriguez Julio; Wohlfert Elizabeth A; Handon Robin; Meylan Francoise; Wu Julie Z; Anderson Stacie M; Kirby Martha R; Belkaid Yasmine; Schwartzberg Pamela L^*

来源：Journal of Experimental Medicine, 2014, 211(3): 529-543.

DOI：10.1084/jem.20131459

A proper balance between Th17 and T regulatory cells (T-reg cells) is critical for generating protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk (IL2-inducible T cell kinase), a component of T cell receptor (TCR) signaling pathways, influences this balance by regulating cross talk between TCR and cytokine signaling. Under both Th17 and Treg cell differentiation conditions, Itk. (-)/(-). CD4+ T cells develop higher percentages of functional FoxP(3+) cells, associated with increased sensitivity to IL-2. Itk(-)/(-) CD4+ T cells also preferentially develop into Treg cells in vivo. We find that Itk- deficient T cells exhibit reduced TCR-induced phosphorylation of mammalian target of rapamycin (mTOR) targets, accompanied by downstream metabolic alterations. Surprisingly, Itk(-)/(-) cells also exhibit reduced IL-2-induced mTOR activation, despite increased STAT5 phosphorylation. We demonstrate that in wild-type CD4+ T cells, TCR stimulation leads to a dose-dependent repression of Pten. However, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and phosphoinositide-3-kinase (PI3K) pathways. Moreover, Itk- deficient CD4+ T cells show impaired TCR-mediated induction of Myc and miR- 19b, known repressors of Pten. Our results demonstrate that Itk helps orchestrate positive feedback loops integrating multiple T cell signaling pathways, suggesting Itk as a potential target for altering the balance between Th17 and Treg cells.

• 出版日期2014-3-10
• 单位NIH