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

Yusuke Yoshimatsu; Tomohisa Sujino; Kentaro Miyamoto; Yosuke Harada; Shun Tanemoto; Keiko Ono; Satoko Umeda; Kosuke Yoshida; Toshiaki Teratani; Takahiro Suzuki; Yohei Mikami; Nobuhiro Nakamoto; Nobuo Sasaki; Kaoru Takabayashi; Naoki Hosoe; Haruhiko Ogata; Kazuaki Sawada; Takeshi Imamura; Akihiko Yoshimura; Takanori Kanai

doi:10.1016/j.celrep.2022.110773

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

Cell Rep. 2022 May 10;39(6):110773. doi: 10.1016/j.celrep.2022.110773.

Authors

Yusuke Yoshimatsu¹, Tomohisa Sujino², Kentaro Miyamoto³, Yosuke Harada¹, Shun Tanemoto¹, Keiko Ono¹, Satoko Umeda¹, Kosuke Yoshida¹, Toshiaki Teratani¹, Takahiro Suzuki³, Yohei Mikami¹, Nobuhiro Nakamoto¹, Nobuo Sasaki⁴, Kaoru Takabayashi⁵, Naoki Hosoe⁵, Haruhiko Ogata⁵, Kazuaki Sawada⁶, Takeshi Imamura⁶, Akihiko Yoshimura⁷, Takanori Kanai⁸

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
² Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan. Electronic address: tsujino1224@keio.jp.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Miyarisan Pharmaceutical Co., Ltd., Tokyo, Japan.
⁴ Institute of Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
⁵ Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan.
⁶ Department of Molecular Medicine for Pathogenesis, Ehime University, Toon, Japan.
⁷ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
⁸ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. Electronic address: takagast@keio.jp.

PMID: 35545035
DOI: 10.1016/j.celrep.2022.110773

Abstract

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.

Keywords: CP: Immunology; MHC class II(+) epithelial cells; aryl hydrocarbon receptor; regulatory T cells; ulcerative colitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colitis, Ulcerative*
Epithelial Cells
Humans
Receptors, Aryl Hydrocarbon*
T-Lymphocytes, Regulatory

Substances

Receptors, Aryl Hydrocarbon