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

• Published in: Journal of molecular and cellular cardiology 2019-10, Vol.135, p.134-148
• Main Authors: Wu, Jian, Sun, Ping, Chen, Qi, Sun, Yong, Shi, Ming, Mang, Ge, Yu, Shan, Zheng, Yang, Li, Zhaoying, Sun, Meng, Fang, Shaohong, Zhang, Yongxiang, Tian, Jinwei, Mingyan, E., Zhang, Maomao, Yu, Bo
• Format: Article
• Language: English
• Subjects: Dilated cardiomyopathy; Glycolytic metabolism; T-cell
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2019.08.002

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.