Aryl hydrocarbon receptor signals in epithelial cells govern the recruitment and location of Helios+ Tregs in the gut

CD4(+) Foxp3(+) regulatory T cells (Tregs) are essential for homeostasis in the colon, but the mechanism by which local environmental cues determine the localization of colonic Tregs is unclear. Here, we administer indigo naturalis (IN), a nontoxic phytochemical aryl hydrocarbon receptor (AhR) agonist used for treating patients with ulcerative colitis (UC) in Asia, and we show that IN increases Helios+ Tregs and MHC class II+ epithelial cells (ECs) in the colon. Interactions between Tregs and MHC class II+ ECs occur mainly near the crypt bottom in the steady state, whereas Tregs dramatically increase and shift toward the crypt top following IN treatment. Moreover, the number of CD25(+) T cells is increased near the surface of ECs in IN-treated UC patients compared with that in patients treated with other therapies. We also highlight additional AhR-signaling mechanisms in intestinal ECs that determine the accumulation and localization of Helios(+) Tregs in the colon.

Automated summary

CD4(+) Foxp3(+) regulatory T cells (Tregs) play a crucial role in the homeostasis of the colon, but the mechanism controlling their localization is still unclear. This study demonstrates that indigo naturalis (IN), an aryl hydrocarbon receptor (AhR) agonist, increases the numbers of Helios+ Tregs and MHC class II+ epithelial cells (ECs) in the colon. Additionally, IN treatment leads to an increase in CD25(+) T cells near the surface of ECs in ulcerative colitis (UC) patients compared to other therapies.