Viral myocarditis involves the generation of autoreactive T cells with multiple antigen specificities that localize in lymphoid and non-lymphoid organs in the mouse model of CVB3 infection

Rakesh H. Basavalingappa, Rajkumar Arumugam, Ninaad Lasrado, Bharathi Yalaka, Chandirasegaran Massilamany, Arunakumar Gangaplara, Jean Jack Riethoven, Shi Hua Xiang, David Steffen, Jay Reddy

Research output: Contribution to journalArticle

Abstract

Autoreactive T cells may contribute to post-viral myocarditis induced with Coxsackievirus B3 (CVB3), but the underlying mechanisms of their generation are unclear. Here, we have comprehensively analyzed the generation of antigen-specific, autoreactive T cells in the mouse model of CVB3 infection for antigens implicated in patients with myocarditis/dilated cardiomyopathy. First, comparative analysis of CVB3 proteome with five autoantigens led us to identify three mimicry epitopes, one each from adenine nucleotide translocator 1 (ANT), sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) and cardiac troponin I. None of these induced cross-reactive T cell responses. Next, we generated major histocompatibility complex (MHC) class II dextramers to enumerate the frequencies of antigen-specific T cells to determine whether T cells with multiple antigen specificities are generated by CVB3 infection. These analyses revealed appearance of CD4 T cells positive for SERCA2a 971−990, and cardiac myosin heavy chain-α (Myhc) 334−352 dextramers, both in the periphery and also in the hearts of CVB3-infected animals. While ANT 21−40 dextramer+ T cells were inconsistently detected, the β1-adrenergic receptor 181−200/211−230 or branched chain α-ketoacid dehydrogenase kinase 111−130 dextramer+ cells were absent. Interestingly, SERCA2a 971−990, Myhc 334−352 and ANT 21−40 dextramer+ cells were also detected in the liver indicating that they may have a pathogenic role. Finally, we demonstrate that the SERCA2a 971−990-reactive T cells generated in CVB3 infection could transfer disease to naïve mice. The data suggest that CVB3 infection can lead to the generation of autoreactive T cells for multiple antigens indicating a possibility that the autoreactive T cells localized in the liver can potentially circulate and contribute to the development of viral myocarditis.

Original languageEnglish (US)
Pages (from-to)218-228
Number of pages11
JournalMolecular Immunology
Volume124
DOIs
StatePublished - Aug 2020

Keywords

  • Autoreactive T cells
  • CVB3
  • MHC dextramers/tetramers
  • Mouse model
  • Viral myocarditis

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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