Figure 3.

Metabolic and transcriptional adaption in tissue Treg cells. VAT-Treg cell accumulation is dependent upon TCR, Foxp3, and IL-33 signaling. VAT macrophages and DCs are the major antigen-presenting cells that express MHC-II to activate and increase VAT-Treg cells. In VAT, white adipose tissue produces IL-33 to increase VAT-Treg cell generation. Leptin produced by adipose cells inhibits VAT-Treg cell proliferation and induces anergy. Leptin-neutralizing antibody reverses anergy and increases mTOR activation and Treg cell proliferation. VAT-Treg cells have high expression of enzyme hydroxyprostaglandin dehydrogenase (HPGD), which is dependent on PPARγ. HPGD produces 15-keto PGE₂ to suppress conventional T cell activation and proliferation. Intestinal Treg cells mainly contain Gata3⁺ tTreg, RORγt⁺, and RORγt⁻ pTreg cells. RORγt⁺ pTreg cells are the dominant population in the colon, while RORγt⁻ pTreg cells mainly localize in small intestine. Their difference is mainly derived from the dominant effect of microbiota and dietary metabolites, respectively, in the colon and small intestine. In the colon, metabolism of tryptophan produces AhR ligands, such as kynurenine, to selectively enhance the generation of Foxp3⁺ Treg cells. In the small intestine, dietary vitamin A is present at high concentrations. RA, a metabolite from vitamin A, induces pTreg cells from naïve T cells in the small intestine in combination with TGF-β. RA also induces the expression of CCR9 on the surface of Treg cells to facilitate their migration to the small intestine. In tumor tissue, Treg cells not only display eTreg cell phenotypes similar to non-lymphoid organs but also express some tumor-specific gene signatures. Compared to conventional T cells, Treg cells have a metabolic advantage in tumor microenvironment, which has low glucose/amino acid, high lactate/hypoxia, and elevated oxidative stress. Genetic or pharmacological perturbation of metabolic pathway PI3K/Akt/Foxo signaling directly impacts tumor-resident Treg cell homeostasis, function and anti-tumor immunotherapy. VAT, visceral adipose tissue; AhR, aryl hydrocarbon receptor.