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Myocarditis is a frequent disease in children and young adults that can precipitate lethal dilated cardiomyopathy (DCM). Since some heart antigens, such as the cardiac myosin heavy chain alpha (myhca) are not represented in the thymus, heart-specific CD4+ T-helper cells are only partially tolerized and can hence elicit a chronic autoimmune disease in this organ. Although stromal cells in the thymus are important for shaping and controlling T cell responses, it has remained elusive how heart-specific thymocytes interact with thymic stromal cells. Furthermore, it is still unknown whether and to which extent lymph node (LN) stromal cell can contribute to the presentation of cardiac autoantigens to CD4+ T cells. In this project, several novel experimental models established in the laboratory of the applicant will be utilized to identify and characterize the central processes involved in the generation and activation of heart-specific Th cells. These models include T cell receptor (TCR) transgenic mice that spontaneously develop myocarditis and progress to DCM, mice that facilitate Cre recombinase-dependent expression of the myhca autoantigen in distinct antigen presenting cells (APCs), and mouse strains with Cre recombinase expression in different thymic and LN stromal cells.

We hypothesize that the critical molecular and cellular processes underlying Th cell-mediated myocardial inflammation are determined by non-hematopoietic stromal cells which impact on the selection and education of heart-specific CD4+ T cells during their development in the thymus and their activation/tolerization in peripheral LNs.

Management of myocarditis and DCM in the clinics suffers from the lack of therapeutic options that attenuate cardiac (auto-)inflammation. We anticipate that the planned studies will help to identify critical effector pathways in the autoimmune components of myocarditis which may guide the development of immune-targeted therapies.