Novel Mouse Models to Study the Role of T Cells in Cardiac Autoimmunity

Myocarditis patients can chronically develop dilated cardiomyopathy and autoreactive T cells could contribute to the disease pathogenesis, but defining their antigen specificity remains a major challenge. To fill this gap, we generated T cell receptor (TCR) transgenic (Tg) mice specific to cardiac myosin heavy chain (Myhc)-α 334–352 and made a few observations. First, we unexpectedly noted both CD4 and CD8 T cells expressing TCRs specific to Myhc-α 334–352. Second, while Tg T cells from myocarditis-resistant C57BL/6J mice did not respond to Myhc-α 334–352, those from immunized mice responded, indicating that in vivo priming is necessary to break tolerance. Third, upon backcrossing Tg mice onto A/J background for four generations, both CD4 and CD8 T cells from naïve mice responded to Myhc-α 334–352 and produced inflammatory cytokines. Fourth, we noted that CD4 T cells exhibited markers of cytotoxicity similar to CD8 T cells. Fifth, although naïve Tg A/J mice did not develop myocarditis spontaneously, fully backcrossed mice could develop the disease. Finally, we studied the development of myocarditis in diversity outbred mice that may have translational significance because their genetic diversity is relatable to the outbred human population. Overall, the availability of various models we have developed are helpful tools to investigate the roles of autoreactive T cell antigens specifically. Advisor: Jay Reddy