Fig. 4. Mechanistic insights into the network between T cell and stem cells. (A) Background information on how CD4^＋ T helper subsets are generated. (B) Each type of CD4^＋ T helper subset plays a distinct role in the fate of intestinal stem cells. Effector cytokines (interferon [IFN]-γ, interleukin [IL]-4, IL-17A) from T helper 1 (Th1), Th2, and Th17 mediated the differentiation of Lgr5^＋ intestinal stem cells, which leads to the generation of goblet cells, tuft cells, and Paneth cells. On the other hand, IL-10 from Tregs induce self-renewal of intestinal stem cells. (C) IL-17 from Tregs promotes the stemness of colorectal cancer by upregulating CD44, CD133, and EpCAM on cancer stem cells (CSCs). Tregs-derived prostaglandin E2 (PGE2) activates NF-κB, expanding CSCs. In hypoxic conditions, transforming growth factor-β (TGF-β) from Tregs induces vascular endothelial growth factor (VEGF), which enhances angiogenesis to nourish CSCs. (D) CSCs secrete IL-23, IL-6, IL-8, IL-1β, which polarize Th17 differentiation. Then, IL-17 and IL-22 from Th17 help, in part, CSC survival. CSCs induce the differentiation and recruitment of Tregs. TGF-β and IDO 1 from CSCs act on naïve CD4^＋ T cells to differentiate into Tregs. CCL2 and CCL5 from CSCs recruit Treg in CCR4 and CCR5-dependent manners. Moreover, CSCs not only upregulate immune checkpoint molecules such as PDL1 and CTLA4 but also reduce MHC I expression, which hinders anti-tumor T cell responses.