Figure 1.

The healthy intestine favors Treg-cell induction in response to harmless antigen and local microenvironmental conditioning maintains the Treg cell phenotype. The mechanisms of intestinal Treg cell induction depend on the structure of the encountered antigen and on the inductive site: in the SI encounter of harmless food antigens predominates eliciting DC-mediated Treg cell induction from naïve T cells. In the colon, commensal microbiota produce SCFA which in presence of TGFβ induce RORγt⁺ Treg cells. In the SI inductive sites, DC-derived TGFβ induction converts circulating naïve T cells into pTreg cells, which is further potentiated by diet-derived RA. Treg cell induction in the SI is CNS1-dependent with a minor contribution from CNS3. In the colon inductive sites, the SCFA induce Treg cells. SCFA induce acetylation of the Foxp3 locus and alter the phenotype of the pTreg cells by increasing RORγt. Moreover, bile acids unconjugated by the microbiome contribute to the induction of colonic RORγt⁺ Treg cells. After induction, pTreg cells migrate from the inductive sites to the LP, where they accumulate and maintain immune homeostasis. In the LP, Treg cells might interact with stromal cells, which receive signals from the microbiome, through a cell-contact dependent mechanism. A portion of the intestinal Treg cells is tTreg cells, induced in the thymus in presence of TGFβ, and that have migrated to the intestine and are highly expressing putative markers for tTreg cells. Finally, a gradient of Treg cells exists increasing from SI to colon. Question marks indicate research areas that remain relatively unexplored.