Both the generation of Treg cells and their expression of gut-homing molecules require that the dendritic cells produce retinoic acid, which is derived from the metabolism of dietary vitamin A through the action of retinal dehydrogenases. Retinoic acid is also produced by stromal cells in the mesenteric lymph node, further enhancing the effects of the migratory dendritic cells. Retinoic acid-producing dendritic cells are also found in Peyer’s patches, and may also be important for generating regulatory T cells either in the Peyer’s patch itself, or after they migrate to the mesenteric lymph node. The induction of regulatory T cells in intestinal tissues is assisted by transforming growth factor-β (TGF-β), which is produced by dendritic cells. Migratory populations of dendritic cells that continuously take up local antigens in the tissue and transport them to the draining lymph nodes are also found in the large intestine and other mucosal surfaces such as the lung. Although it is believed dendritic cells from these tissues are also involved in maintaining tolerance to harmless materials such as commensal bacteria, they do not produce retinoic acid, and it is not clear how they influence T-cell differentiation and homing.
The dendritic cells in the intestinal lamina propria also include the two major subsets described above. Collectively, the properties of intestinal dendritic cells result in a dominantly tolerogenic environment that prevents unnecessary and damaging reactions to foods and commensal microorganisms. The anti-inflammatory behavior of mucosal dendritic cells in the healthy gut is promoted by factors that are constitutively produced in the mucosal environment. These include thymic stromal lymphopoietin (TSLP), TGF-β produced by dendritic and epithelial cells, prostaglandin PGE2 produced by stromal cells, and IL-10 produced by intestinal macrophages and CD4 T cells. Retinol stored in the liver and delivered into the small intestine via the bile provides an additional source for the local generation of retinoic acid for conditioning dendritic cells in the wall of the small intestine.
12-8 Macrophages and dendritic cells have different roles in mucosal immune responses.
The lamina propria of the healthy intestine contains the largest population of macrophages in the body. Like dendritic cells, they express CD11c and class II MHC, but unlike dendritic cells in this site, they lack CD103 expression, but express FcγR1 (CD64; see Fig. 10.38) and CX3CR1, the receptor for CX3CL1 (fractalkine). Macrophages are also unable to migrate from the intestine to the draining lymph nodes and cannot present antigen to naive T cells. Unlike many other tissue-resident macrophages, such as those in the brain or liver, which develop from embryonic precursors (see Section 3-1), those in the intestine require constant replenishment by blood monocytes.