Localization of CD8 T cell epitope within cardiac myosin heavy chain-α_334-352 that induces autoimmune myocarditis in A/J mice

Authors

Chandirasegara Massilamany, University of Nebraska-LincolnFollow
Arunakumar Gangaplara, University of Nebraska - Lincoln
Rakesh H. Basavalingappa, University of Nebraska-LincolnFollow
Rajkumar A. Rajasekaran, University of Nebraska - Lincoln
Vahid Khalilzad-Sharghi, University of Nebraska-LincolnFollow
Zhongji Han, University of Nebraska - Lincoln
Shadi F. Othman, University of Nebraska - LincolnFollow
David Steffen, University of Nebraska-LincolnFollow
Jay Reddy, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

2016

Citation

Int J Cardiol. 2016 January 1; 202: 311–321.

Comments

Copyright 2016 Elsevier.

Abstract

Background—Cardiac myosin heavy chain-α (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-2a), we discovered that Myhc_334-352, supposedly a CD4 T cell epitope, also induced antigen-specific CD8 T cells that transfer disease to naïve 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-2Dd – but not H-2Kk or H-2Ld – alleles. (3) The CD8 T cell response induced by Myhc_338-348 was antigen-specific, as evaluated by MHC class I/H-2Dd dextramer staining. The antigen-sensitized T cells predominantly produced interferon-γ, 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.