Figure 1. Antigen Specific and Non-Specific Mechanisms of Bacteria-Induced Treg Cell Generation and Function.

Clostridium spp. establish an environment favorable for pTreg cell generation via the induction of TGFβ secretion by intestinal epithelial cells (IECs) (purple arrow), IDO in IECs and APCs (red arrows), and the production of SCFAs from dietary components (blue). Bacteroides spp. such as B. fragilis have been described to increase Treg cell function through PSA activation of TLR2 ligation on T cells and DCs (grey arrows). PSA, as well as SCFAs (blue arrow), induce IL-10 secretion from LP Treg cells. SCFAs also act directly on T cells to induce Treg differentiation/expansion. Dietary vitamin A from the intestinal lumen (orange arrows) can enhance pTreg cell differentiation through its metabolite retinoic acid, which can affect pTreg cell selection by inducing transcription factor binding to a Foxp3 enhancer element in CNS1^48-50, or via blockade of effector cytokine production by effector T cells¹²⁹. Bacterial antigens (green arrow), may gain access to immune cells by a variety of mechanisms that are currently unclear, including via goblet-associated passages, transcytosis through IECs, extension of APC processes into the intestinal lumen, or direct invasion of whole bacteria^{130, 131}. Naïve T cells have been reported to encounter commensal antigens in the mesenteric lymph node and undergo pTreg cell selection³³. The Peyer's patches and isolated lymphoid follicles may also be important sites of pTreg cell selection, but this requires further study.