Fig. 2
From: New insights into the stemness of adoptively transferred T cells by γc family cytokines
The signaling pathways mediated by the four γc family cytokines regulate T cell stemness. The stemness of T cells is cooperated by several signaling pathways. The four γc family cytokines trigger the JAK-STAT, RAS-MAPK, and PI3K-AKT signaling pathways to collectively modulate TSCM phenotype induction. IL-2 combines with high-affinity IL-2R via dimeric STAT5 to induce terminal differentiation whereas reduced STAT5 signaling by intermediate-affinity IL-2R can increase the expression of memory- and antiapoptotic-associated molecules. IL-7 and the trans-presented IL-15 also activate STAT5 phosphorylation to initiate the expression of the stem-like markers such as CD95, TCF1, and CD62L, for persistent survival and TSCM cell induction. IL-21 mainly activates the phosphorylation of STAT1 and STAT3, the latter of which induces the expression of Scal-1, CD95, TCF1 and CD62L, thereby contributing to TSCM phenotype formation. The activation of P70S6K via PI3K-AKT and mTOR is involved in T cell differentiation; therefore, inhibitors of the AKT pathway, such as AKT inhibitors and mTOR inhibitor Rapamycin, provide opportunities to regulate stemness. WNT inhibits GSK3β to release β-catenin into the nucleus to regulate the expressions of Bcl-2, c-Myc, c-Jun, CD62L and TCF1 to promote TSCM formation, the same as the GSK3β inhibitor TWS119. In addition, the activation of the Notch and cGAS-STING pathways can also promote T cell stemness