In addition to CD8+ IELs, the gut also hosts γδTCR T cells, NKT cells, and classical CD4+ T cells with αβTCR. The exact immune function of all these cells is unknown. The general tendency of these lymphocytes is to generate a tolerogenic immune response to antigens encountered in the gut lumen (20, 21). Other cellular types also participate in mounting an immune response. The most important for promoting oral tolerance are dendritic cells in the lamina propria, which infiltrate the area between

the latero-basal sides of the enterocytes and reach into the intestinal lumen with their projections, taking up antigens which are afterwards processed and presented into the mesenteric lymph nodes (22). Another important cell EMD 1214063 chemical structure is the so-called M cell, placed as a hood over the luminal region of the PP. These M cells are in contact with Epacadostat purchase the gut content at their upper pole, allowing them to capture antigens and pass them over to the

immune milieu of the PP, where they are processed by other dendritic cells and then presented to lymphocytes in the local lymph nodes (23). It has been proved that a large proportion of intestinal dendritic cells express an enzyme called retinal dehydrogenase, (responsible for vitamin A metabolism), which produces a shift toward a tolerogenic phenotype in the case of the T helper cells that interact with these dendritic cells (24, 25). All these particularities of the enteric immune system result in generation, at the intestinal level, of Th regulatory cells, also known as iTreg, Tr1, Th3 and Th2 (26). Although intestinal T regulatory cells C-X-C chemokine receptor type 7 (CXCR-7) are classical CD4+CD25+FoxP3+ regulatory cells, they appear in

the intestine, and not in the thymus (27). Tr1 (CD4+ IL-10+ FoxP3-) are regulatory cells which exert their function especially through the synthesis of IL-10, while Th3 (CD4+ TGF-β+ FoxP3+) rely on the release of TGF-β for the down regulation of immune responses. These regulatory subpopulations present numerous interconnections in vivo, probably leading to the existence of intermediate cellular types (28). All these characteristics make the gut a predominantly tolerogenic immune environment. The oral administration of any peptide can have three consequences: the secretion of anti-peptide IgA; a systemic immune response with the appearance of serum antibodies and cell-mediated immunity; or a state of anergy, local and/or general tolerance, which prevents an unwanted immune response when re-encountering an innocuous antigen. The first two situations are encountered in the case of pathogens with invasive potential, while the third possibility applies to commensal bacteria and dietary antigens, which do not cause local injuries or systemic immune responses (29).