Figure 2. The role of retinoic acid in the regulation of CD4⁺ T cell homeostasis and immunity in the GI tract.

The GALT is a retinoic acid (RA) rich environment, containing a vast presence of RA synthesizing cells, including: resident epithelia (IEC) and stroma (SC), as well as migratory CD103⁺ DCs. RA produced by IEC may confer characteristic features to Lp DCs, while RA produced by SC in the draining mesenteric lymph nodes may reinforce lymphocyte acquisition of mucosal homing markers and potentially other effector functions. (A) During steady-state conditions RA sustains oral tolerance and helps maintain barrier integrity. These processes are mediated in large part by the ability of RA to support the induction of Foxp3⁺ iTreg and Th17 cells. Lamina propria CD103⁺ DCs are important for the induction and recruitment of heterogeneous CD4⁺ T cell populations during steady-state, as result of their ability to respond to commensal microbial signals and produce both RA and TGF-β. This dual capacity likely involves autocrine, or paracrine, RA signaling through retinoic acid receptors, such as RARα, which drives RA synthesis. An RA rich intestinal milieu also potentially limits the pathogenic potential and turnover of Th17 cells through down regulation of IL-6R and IL-23R. (B) During inflammation or infection, the inflammatory milieu triggers altered cytokine production by CD103⁺ DCs, leading to RARα-dependent effector CD4⁺ T cell activation and differentiation. Innate cell populations, including antigen presenting cells, are recruited during inflammation and may support RA production. Factors in the inflammatory milieu including TLR-ligands and the cytokine, GM-CSF, promote RALDH activity in CD103⁺ DCs and potentially in recruited innate cells.