An evidence for surface expression of an immunogenic epitope of sarcoplasmic/endoplasmic reticulum calcium-ATPase2a on antigen-presenting cells from naive mice in the mediation of autoimmune myocarditis
Date of this Version
Published in final edited form as: Immunobiology. 2020 March ; 225(2): 151896. doi:10.1016/j.imbio.2019.12.005.
HHS Public Access Author manuscript: Immunobiology. Author manuscript; available in PMC 2021 March 01.
We recently reported identification of sarcoplasmic/endoplasmic reticulum calcium-ATPase2a (SERCA2a) 971–990, which induces atrial myocarditis by generating autoreactive T cells in A/J mice. However, it was unknown how antigen-sensitized T cells could recognize SERCA2a 971–990, since SERCA2a-expression is confined to an intracellular compartment. In this report, we present evidence that antigen-presenting cells (APCs) from lymphoid and non-lymphoid organs in naïve animals present SERCA2a 971–990 and stimulate antigen-specific T cells. Using major histocompatibility complex (MHC) class II dextramers for SERCA2a 971–990, we created a panel of T cell hybridomas and demonstrated that splenocytes from naïve A/J mice stimulated the hybridoma cells without exogenous supplementation of SERCA2a 971–990. We then recapitulated this phenomenon by using SERCA2a 971–990-specific primary T cells, verifying that the T cell responses were MHC-restricted. Furthermore, SERCA2a 971–990-sensitzed T cells exposed to APCs from naïve mice were found to produce the inflammatory cytokines interferon-γ, granulocyte macrophage colony stimulating factor, and interleukin-17A, which are implicated in the induction of myocarditis. Finally, while T cells exposed to mononuclear cells (MNCs) obtained from heart and liver also responded similarly to splenocytes, endothelial cells (ECs) generated from the corresponding organs displayed opposing effects, in that the proliferative responses were suppressed with the heart ECs, but not with the liver ECs. Taken together, our data suggest that the surface expression of SERCA2a 971–990 by naïve APCs can potentially trigger pathogenic autoreactive T cell responses under conditions of autoimmunity, which may have implications in endothelial dysfunction.
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