T cell regulation and reactivity to organ-specific antigens

Because of their central role in coordinating adaptive immune responses, CD4+ T cells are a critical component of the host defense against infection. Unfortunately, dysregulated CD4+ T cell responses have also been identified as an important mechanism by which harmful autoimmune responses against self antigens are generated. The overall goal of this study has been to understand how T cell tolerance to organ-specific antigens is acquired and how breakdown of these regulatory processes may lead to organ specific autoimmune disease. To do this, we utilized an experimental system in which lineages of mice had expression of the transgenic neo-self antigen influenza hemagglutinin (HA) targeted to the myocardium using the tissue-specific promoter for β-myosin. Despite use of this promoter, HA transgenic mice were found to have some detectable expression of HA in other tissues, including the thymus. HA specific CD4+ T cells developing in these mice were subject to intrathymic regulation, namely by deletion and functional inactivation. Thymic expression of HA was found to be necessary for regulation of developing HA-specific thymocytes via either of these two mechanisms and expression by thymic stroma was found to be necessary for anergy induction. The susceptibility of a developing HA-specific thymocyte to intrathymic regulation was determined by the affinity of interaction between the thymocyte and self antigen. HA-specific CD4+ T cells escaping intrathymic regulation caused spontaneous autoimmune myocarditis in these mice, and were not subject to active regulatory processes in the periphery. Finally, the pathogenic potential of HA-specific CD4+ T cells to mediate autoimmune myocarditis was greatly influenced by T helper subset differentiation, with Th1 subset cells generating more destructive inflammatory processes, in part due to specialized C-C chemokine secretion. These findings indicate that the regulation of autoreactive T cells is dependent upon the nature of their interaction with self peptides during development within the thymus. In the absence of such intrathymic interactions, active T cell regulatory mechanisms in the periphery are less protective. Finally, our finding of polarized chemokine secretion by autoaggressive Th1 cells reveals a mechanism by which T helper subsets coordinate recruitment of disparate effector cell populations and suggests novel pathways for the design of immune-based therapies.