Knockdown of miR-146a in regulatory T cells suppresses heart transplantation rejection in mice by increasing autophagy

Abstract

Clinical trials of regulatory T cells (Tregs) have shown that adoptive transfer of Tregs has great promise for the treatment of rejection. However, strategies to improve Treg function are needed in order to enhance their efficacy and reduce the number of Tregs required for adoptive transfer. Autophagy is a process for degrading intracellular components, and it mediates cell death, lymphocyte homeostasis, and Treg function. Studies have shown that the survival and function of Tregs with disrupted autophagy are defective. We found that the autophagic status of Tregs was compromised during acute rejection, allowing us to enhance Treg autophagy by regulating microRNA-146a (miR-146a), which is highly expressed in Tregs and is implicated in their function and metabolism. MiR-146a antagomir-mediated miR-146a knockdown promoted Treg autophagy, as evaluated by Western blot analysis. Further, we evaluated whether altering autophagy affects Treg function in both an in vitro cell coculture model and a heart transplantation model in mice. An increase in autophagy enhanced the inhibitory effects of Tregs on CD4+ T cells and dendritic cells (DCs) in vivo and in vitro. In addition, adoptive transfer of highly autophagic Tregs treated with miR-146a antagomir significantly alleviated rejection. Collectively, these data provide a new method that uses miR-146a knockdown to increase Treg efficacy by increasing autophagy.