Figure 1.

Immunoregulatory circuits in the gut mucosa triggered by food components. Food proteins are absorbed either as intact molecules by transcellular transport through specialized microfold cells (M cells) or as peptides by paracellular transport across the epithelial cells. Dendritic cells (DC) and macrophages underlying epithelial cells in Peyer’s patches and in lamina propria take up these antigens and present them inside molecules of class II major histocompatibility complex (MHC II) to naïve CD4⁺ T cells. Most of antigen presentation in the gut mucosa is performed by DCs since resident macrophages have low levels of MHC II. Mucosal CD103⁺ DCs express the enzyme retinal dehydrogenase (RALDH) that convert food-derived vitamin A (retinol) into retinoic acid (RA). Antigen presentation by RA-producing DCs in the presence of TGF-β is able to differentiate naive CD4⁺ T cells into CD4⁺CD25⁺Foxp3⁺ regulatory T cells. Mucosal macrophages have also been shown to produce RA and participate in the generation of Foxp3⁺ Tregs. RA induces expression of α4β7 and CCR9 in T cells imprinting them with gut-homing properties (CD4⁺ and CD8⁺ T cells). RA also induces the expression of NFATc1 in B1 cells, a transcription factor implicated in the development and survival of these cells. TGF-β is an abundant cytokine in the mucosal milieu being secreted by a variety of cells such as epithelial cells, macrophages, DCs, and T cells. This anti-inflammatory cytokine is fundamental for the maintenance of the tolerogenic environment of the gut and it contributes to the differentiation of a number of Tregs such as CD4⁺Foxp3⁺, CD4⁺LAP⁺ T cells as well as TGF-β-secreting Th3 cells. IL-10 is another key cytokine for the maintenance of gut homeostasis and it is produce by several cell types (macrophages, DCs, CD4+ Tr1 cells, and B1 cells). IL-10 modulates macrophage function, helps the differentiation of Th3 cells, and stabilizes the expression of Foxp3 in CD4⁺Foxp3⁺ Tregs. CD4⁺Foxp3⁺ can be converted into follicular helper T cells (TFH) in Peyer’s patches with the help of IL-6 and IL-21. Lipids have also modulatory effects in the gut mucosa by interacting with intracellular PPAR-γ receptors in macrophages. Short chain fatty acids (SCFA) bind to GPR41 or GPR43 metabolic sensors in the epithelial cell surface downmodulating inflammatory responses. Glycolipids may also function as antigens presented by epithelial cells or DCs in CD1d molecules stimulating NKT cells that are able to secrete large amounts of IL-4 and IFN-γ.