Oral tolerance: is it all retinoic acid?

Abstract

Oral tolerance has been argued to depend on "special" presentation of antigen in the gut. New studies support this idea by showing that the catalysis of vitamin A into retinoic acid (RA) in gut-associated dendritic cells (DCs) enhances the transforming growth factor (TGF)-beta-dependent conversion of naive T cells into regulatory T (T reg) cells and also directs T reg cell homing to the gut. These results reveal new tolerance mechanisms that will aid the use of T reg cells in the clinic.

Figure 1.

RA promotes the differentiation of FoxP3⁺ T reg cells in the gut. Antigen from the gut lumen gains access to CD103⁺ gut-associated DCs. T cells that recognize antigen in the context of DC-produced RA and TGF-β up-regulate Foxp3 and become T reg cells.

Figure 2.

Model of gene regulation that leads to the differentiation of T helper type 17 or T reg cells. TCR stimulation and co-stimulation of T cells results in NFAT and AP-1 activation, which form a DNA binding complex that regulates gene expression. TGF-β signaling results in phosphorylation and nuclear translocation of TGF-β–associated Smad proteins, and IL-6 signaling activates Stat3. These signals combine to promote differentiation into T helper type 17 (Th17) effector cells. In the absence of co-stimulation and/or the presence of RA, AP-1 is not produced. In the absence of IL-6, Stat3 is not activated. Without AP-1 and Stat3, the cell converts into a Foxp3-expressing T reg cell in a TCR and TGF-β signaling-dependent manner.