CD28-ITK signals regulate autoreactive T cell trafficking into tissues (123.41)

Abstract

Abstract Autoimmune diseases such as Type 1 diabetes arise from the activation of self- reactive T cells and their trafficking to target tissues, ultimately leading to impaired organ function. Immune-based therapies for autoimmunity including corticosteroid regimens, modulation of inflammatory effectors and tolerance induction by inhibition of T cell activation fail to target self-reactive T cells specifically, resulting in compromised general immunity. A recent focused approach aims at regulating self-reactive T cell migration to organs to limit immune pathology. The signaling pathways regulating migration of activated tissue-antigen specific T cells versus activated foreign-antigen specific T cells are unknown. Here we demonstrate that the B7-CD28 costimulatory pathway of T cell activation is an important regulator of the trafficking of self-reactive T cells. The Tec-kinase ITK is a downstream mediator of the CD28 signal controlling autoreactive T cell migration. Using the Ctla4-/- mouse as a model of multi-organ autoimmunity, we show that genetic and pharmacological inhibition of ITK prevents the migration of activated T cells into target tissues. Furthermore, small molecule ITK inhibitors prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of type I diabetes. Our results suggest that pharmacological disruption of ITK function should be considered as a treatment of human T cell mediated organ-specific autoimmune diseases.