Complex role for Interleukin-2 inducible T-cell kinase in T helper differentiation and effector function in vivo (P1204)

Abstract

Abstract T helper responses are critical for a productive immune response but an inappropriate response results in inflammatory and autoimmune disorders. The tyrosine kinase ITK has been shown to regulate the development of Th2 responses. Here, we show that ITK regulates Th1/Th17 responses as well. We find that Itk-/- mice are more susceptible to infection by Th1 inducing intracellular pathogen T. gondii, with generation of fewer antigen specific Th1 cells in vivo and fewer effector cells ex vivo upon antigen re-challenge. Transfer of WT CD4+ T cells confers protection against infection in Itk-/- mice. Furthermore, WT but not Itk-/- CD4+ T cells can promote the survival of Rag-/- mice infected by T. gondii. Additionally, the absence of ITK is protective during Th1/Th17 mediated Experimental Autoimmune Encephalomyelitis (EAE) with fewer pathogenic Th1 and Th17 effector cells in the periphery. Furthermore, transfer of Itk-/- CD4+ T cells into Tcra-/- mice results in lower severity of EAE compared to mice that receive WT cells suggesting that Itk-/- CD4+ T cells are intrinsically less pathogenic. Finally, using mice that express an analog sensitive mutant of ITK (ITKas) we show that temporally inhibiting the kinase activity of ITK with a genetically selective small-molecule inhibitor impairs development of Th1, Th2, and Th17 lineages. This work has implications for understanding ITK as a therapeutic target for Th2 mediated inflammatory and Th1/Th17 mediated autoimmune disorders.