Cardiac myosin-specific TCR transgenic mouse models for studying dilated cardiomyopathy

Abstract

Abstract We previously reported that the cardiac myosin heavy chain-alpha (Myhc) 334–352 encompasses epitopes for both CD4 and CD8 T cells that can induce autoimmune myocarditis/dilated cardiomyopathy (DCM) in A/J mice expressing the IAk and IEk molecules. More recently, we made an unexpected observation that, Myhc 334–352 although by being a poor binder of IAb molecule in C57Bl/6 mice, could induce strong T cell responses, but myocarditogenicity was severely dented. In our efforts to delineate the roles of Myhc-specific, CD4 and CD8 T cells in the DCM pathogenesis, we have now created the T cell receptor (TCR) transgenic (tg) mice on C57Bl/6 background for Myhc 334–352, and demonstrate that the Myhc 334–352-specific TCR was found common to both CD4 and CD8 T cells. While, the naïve tg T cells do not respond, antigen-primed CD4 and CD8 T cells from immunized mice respond to Myhc 334–352 that produce predominantly, interferon-γ. Furthermore, although mild, the immunized tg mice developed heart lesions containing the mononuclear cells, and such a phenotype was more apparent in females than males. As the tg mice become available on both resistant (C57Bl/6) and susceptible (A/J) backgrounds, our TCR tg system can be used as a helpful tool to dissect the complexities of antigen-specific CD4 and CD8 T cells in the causation of DCM in various experimental settings.