CD28 and ITK signals regulate autoreactive T cell trafficking

Activation of self-reactive T cells and their trafficking to target tissues leads to autoimmune organ destruction. Mice lacking the coinhibitory receptor CTLA-4 develop fatal autoimmunity characterized by massive lymphocytic invasion into non-lymphoid tissues. Here we demonstrate that the CD28 costimulatory pathway regulates the trafficking of self-reactive Ctla4(−/−) T cells to tissues. Co-ablation of the CD28-activated Tec family kinase ITK does not block spontaneous T cell activation, but instead causes self-reactive Ctla4(−/−) T cells to accumulate in secondary lymphoid organs. Despite a fulminant autoimmune process in the lymphoid compartment, Itk(−/−)Ctla4(−/−) mice are otherwise healthy and exhibit a long lifespan. We propose that ITK licenses autoreactive T cells to enter tissues to mount destructive immune responses. Importantly, ITK inhibitors mimic the null mutant phenotype and also prevent pancreatic islet infiltration by diabetogenic T cells in mouse models of Type I diabetes, highlighting their potential utility for the treatment of human autoimmune disorders.