Sulfated bile acid is a host-derived ligand for MAIT cells.

Ito, Emi; Inuki, Shinsuke; Izumi, Yoshihiro; Takahashi, Masatomo; Dambayashi, Yuki; Ciacchi, Lisa; Awad, Wael; Takeyama, Ami; Shibata, Kensuke; Mori, Shotaro; Mak, Jeffrey Y. W.; Fairlie, David P.; Bamba, Takeshi; Ishikawa, Eri; Nagae, Masamichi; Rossjohn, Jamie; Yamasaki, Sho

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin–based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue–derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes (Sult2a1-8) responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function. Editor's summary: Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset important for mucosal homeostasis, which recognize microbiota-derived vitamin B metabolites presented by the MHC-Ib molecule MR1. It is unclear, however, whether any host-derived ligands are also important for MAIT cell function and survival. Ito et al. report that the host-derived bile acid metabolite cholic acid 7-sulfate (CA7S) binds MR1 and is recognized by MAIT cells in mice. Moreover, genetic deletion of sulfotransferase 2a enzymes (Sult2a1-8) needed for its synthesis in mice reduced thymic MAIT cell numbers. A previously characterized vitamin B metabolite, 5-OP-RU, triggered human MAIT cell proliferation and the expression of inflammatory genes. By contrast, CA7S promoted human MAIT cell survival and a gene program associated with wound healing and immunoregulation. —Seth Thomas Scanlon

BILE acids; T cell receptors; CHOLIC acid; CELL physiology; BACTERIAL metabolites; VITAMIN B complex; DEOXYCHOLIC acid

Science Immunology, 2024, Vol 9, Issue 91, p1

2470-9468

Academic Journal

10.1126/sciimmunol.ade6924