Astilbin promotes the induction of regulatory NK1.1− CD4+ NKG2D+ T cells through the PI3K, STAT3, and MAPK signaling pathways

Astilbin is a potential agent for autoimmune and inflammatory diseases and has a protective effect in mice with DSS-induced colitis. NK1.1− CD4+ NKG2D+ T cells are a subpopulation of regulatory T cells that produce TGF-β1 and IL-10. Whether astilbin directly promotes the induction of NK1.1− CD4+ NKG2D+ T cells and whether these astilbin-stimulated T cells exert an immune-regulatory role remain unclear. Here, we show that astilbin efficiently induces the production of NK1.1− CD4+ NKG2D+ T cells with high expressions of TGF-β1, IL-10, CCR6, and CCR9 in a dose-dependent manner ex vivo. These regulatory T cells also substantially inhibit the activities of CD8+ T cells and macrophages. Intraperitoneal injection of astilbin ameliorates the severity of colitis with an increase in the frequency of NK1.1− CD4+ NKG2D+ T cells in the colon tissue of DSS-treated mice. Moreover, adoptive transfer of NK1.1− CD4+ NKG2D+ T cells induced by astilbin remarkably protects against the onset of DSS-induced colitis. Finally, the PI3K, STAT3, and MAPK signaling pathways are involved in the induction of NK1.1− CD4+ NKG2D+ T cells by astilbin. Taken together, our study elucidates a new immune-regulatory mechanism of astilbin by inducing the regulatory NK1.1− CD4+ NKG2D+ T cells and indicates a potential clinical use of astilbin for patients with inflammatory bowel diseases.