Localization of CD8 T cell epitope within cardiac myosin heavy chain-alpha(334-352) that induces autoimmune myocarditis in A/J mice

Background: Cardiac myosin heavy chain-alpha (Myhc), an intracellular protein expressed in the cardiomyocytes, has been identified as a major autoantigen in cardiac autoimmunity. In our studies with Myhc(334-352)-induced experimental autoimmune myocarditis in A/J mice (H-2(a)), we discovered that Myhc(334-352), supposedly a CD4 T cell epitope, also induced antigen-specific CD8 T cells that transfer disease to naive animals. Methods and results: In our efforts to identify the CD8 T cell determinants, we localized Myhc(338-348) within the full length-Myhc(334-352), leading to four key findings. (1) By acting as a dual epitope, Myhc(338-348) induces both CD4 and CD8 T cell responses. (2) In a major histocompatibility complex (MHC) class I-stabilization assay, Myhc(338-348) was found to bind H-2D(d)-but not H-2K(k) or H-2L(d)-alleles. (3) The CD8 T cell response induced by Myhc(338-348) was antigen-specific, as evaluated by MHC class I/H-2D(d) dextramer staining. The antigen-sensitized T cells predominantly produced interferon-gamma, the critical cytokine of effector cytotoxic T lymphocytes. (4) Myhc(338-348) was found to induce myocarditis in immunized animals as determined by histology and magnetic resonance microscopy imaging. Conclusions: Our data provide new insights as to how different immune cells can recognize the same antigen and inflict damage through different mechanisms. (C) 2015 Elsevier Ireland Ltd. All rights reserved.