Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice

J Mol Cell Cardiol. 2019 Oct:135:134-148. doi: 10.1016/j.yjmcc.2019.08.002. Epub 2019 Aug 6.

Abstract

Cellular autoimmune responses, especially those mediated by T-cells, play vital roles in the immunopathogenesis of dilated cardiomyopathy (DCM). Metabolic reprogramming directly controls T-cell function, imprinting distinct functional fates. However, its contribution to T-cell dysfunction and the immunopathogenesis of DCM is unknown. Here, we found that in DCM patients, CD4+ T-cells exhibited immune dysfunction and glycolytic metabolic reprogramming based on extracellular acidification and oxygen consumption rates. Similar results were observed in splenic and cardiac CD4+ T-cells from autoimmune-induced DCM mice. In vitro, the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) reversed T-cell dysfunction; thus, heightened metabolic activity directly controls CD4+ T-cell immunological status. Adoptive transfer of CD4+ T-cells from DCM mice to normal recipients induced cardiac remodeling and cardiac T-cell dysfunction. Strikingly, these effects were abolished by preconditioning cells with 2-DG, indicating that CD4+ T-cell dysfunction partially induced by metabolic reprogramming contributes to cardiac remodeling. Moreover, the microRNA let-7i modulated the metabolism and function of T-cells from DCM mice by directly targeting Myc. Collectively, our results show that metabolic reprogramming occurs in T-cells of autoimmune-induced DCM mice and patients. Further, our findings highlight that glycolytic metabolism is a critical contributor to T-cell dysfunction and DCM immunopathogenesis. Our data position the modulation of the metabolism as a central integrator for T-cell function, representing a promising strategy against autoimmune-mediated DCM progression.

Keywords: Dilated cardiomyopathy; Glycolytic metabolism; T-cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • Cardiomyopathy, Dilated / immunology*
  • Cardiomyopathy, Dilated / pathology
  • Cellular Reprogramming / genetics
  • Cellular Reprogramming / immunology*
  • Disease Models, Animal
  • Humans
  • Mice
  • MicroRNAs / genetics
  • Proto-Oncogene Proteins c-myc / genetics
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology

Substances

  • MYC protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • mirnlet7 microRNA, mouse