FIGURE 2.

ICOS signaling pathway in Tregs. ICOS-ICOSL interaction promotes the generation, proliferation, survival and suppressive ability of regulatory T cells (Tregs) through complex signaling pathways. First, activation of ICOS promotes Foxp3 transcription, favoring NFAT binding to FOXP3 over AP-1 and upregulating FOXP3 downstream regulatory genes, such as Il-10 and Tgf-β. Second, ICOS engagement induces PI3K recruitment to the YMFM motif at the cytoplasmic tail and the phosphorylation of Akt. Activation of Akt can induce Bcl-2 expression and inhibit pro-apoptotic Bcl-2 family protein production, thereby promoting ICOS⁺ Treg survival. Furthermore, ICOS also activates the mTORC1 signals, which is suggested to mediate protein synthesis and metabolism in Tregs. In addition, ICOS expression elevates CXCR3 expression, which promotes the migration of Tregs to inflammatory tissues.