Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis

Abstract

Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.Electronic supplementary materialThe online version of this article (10.1007/s00395-019-0766-6) contains supplementary material, which is available to authorized users.

Immunomodulatory Role of Tenascin-C in Myocarditis and Inflammatory Cardiomyopathy

“…In contrast to the well-defined cardiac antigen-specific T-cell responses, our understanding of the role of heart non-specific CD4 + T cells in myocarditis is limited. Recently, Zarak-Crnkovic et al ( 36 ) demonstrated in a proof-of-concept study that heart non-specific effector T cells did not affect the severity of myocarditis, but protected the heart from adverse post-inflammatory fibrotic remodeling and cardiac dysfunction in the chronic stage. Moreover, bystander activation of effector T cells suppressed the myofibroblast phenotype of mouse and human cardiac fibroblasts ( 36 ), suggesting a dynamic and complex role of effector T cells and the interplay between T cells and fibroblasts in autoimmune myocarditis.…”

Circle the Cardiac Remodeling With circRNAs

“…It manifests as deposition of scar, increasing stiffness, decreasing contraction and impaired heart function, which ultimately resulting in heart failure (116). Although, cardiac fibrosis is a complex process and involves many types of cells in the heart, such as cardiomyocytes, fibroblasts, lymphocytes, and pericytes (117)(118)(119), extensive studies have proved that cardiac fibroblasts (CFs) play a pivotal role in this process (120). When suffered cardiac injury, the proliferation and migration of CFs are increased.…”

A model informed approach to assess the risk of checkpoint inhibitors induced myocarditis

“…These cells accumulate throughout disease progression and become the major infiltrating subset at a later stage, after the peak of inflammation has passed. Their function lies in protecting the heart from post-inflammatory fibrotic remodelling, thus decreasing the risk of severe negative outcomes such as dilated cardiomyopathy and cardiac dysfunction, which are further discussed in Section d (Zarak-Crnkovic et al, 2020). Function: T regulatory cells.…”