Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice.
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.
['Wu|Jian|J|', 'Sun|Ping|P|', 'Chen|Qi|Q|', 'Sun|Yong|Y|', 'Shi|Ming|M|', 'Mang|Ge|G|', 'Yu|Shan|S|', 'Zheng|Yang|Y|', 'Li|Zhaoying|Z|', 'Sun|Meng|M|', 'Fang|Shaohong|S|', 'Zhang|Yongxiang|Y|', 'Tian|Jinwei|J|', 'Mingyan|E|E|', 'Zhang|Maomao|M|', 'Yu|Bo|B|']
D000818:Animals D015551:Autoimmunity D015496:CD4-Positive T-Lymphocytes D002311:Cardiomyopathy, Dilated D065150:Cellular Reprogramming D004195:Disease Models, Animal D006801:Humans D051379:Mice D035683:MicroRNAs D016271:Proto-Oncogene Proteins c-myc D013601:T-Lymphocytes
T-cell Dilated cardiomyopathy Glycolytic metabolism