Role of miR-449a in the Activation and Metabolism of CD4+ T Cells

Abstract

BackgroundAcute rejection is a significant challenge after organ transplantation. The CD4+ T-cell‒mediated immune response plays an important role in acute transplant rejection. It was also found that miR-449a microRNA regulates the alloimmune response in a model of heart transplantation in mice. Our goal was to determine the role of miR-449a in the regulation of CD4+ T cells. MethodsWe examined miR-449a expression in peripheral blood mononuclear cells (PBMCs) and graft-infiltrating lymphocytes (GILs) between syngeneic transplant and allogeneic transplant groups on day 7 post‒heart transplantation. We also examined miR-449a expression in CD4+ T-cell activation and mixed-lymphocyte reactions (MLRs) in vitro. To evaluate the effect of miR-449a on CD4+ T-cell metabolism, we analyzed key metabolic parameters using XFp extracellular flux analyses. ResultsOur in vivo heart transplant models showed that the expression of miR-449a in PBMCs and in GILs significantly increased in the allogeneic groups in comparison to the syngeneic groups (P < .01). Furthermore, in vitro analysis confirmed that the expression of miR-449a was significantly elevated in activated CD4+ T cells. Reduction of miR-449a expression in CD4+ T cells decreased the mitochondrial respiration in the same CD4+ T cells. ConclusionOur results reveal that miR-449a microRNA was elevated in allogeneic heart allografts. This correlated with an increased miR-449a expression in activated CD4+ T cells. Inhibition of miR-449a in activated CD4+ T cells coincided with reduced mitochondrial respiration, suggesting that miR-449a influences CD4+ T-cell activation during the alloimmune response by regulating metabolic status.