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

• DOI: 10.1126/sciimmunol.ade6924
• Publication Date: 2024-01-26T18:59:11Z
• Authors: Emi Ito; Shinsuke Inuki; Yoshihiro Izumi; Masatomo Takahashi; Yuki Dambayashi; Lisa Ciacchi; Wael Awad; Ami Takeyama; Kensuke Shibata; Shotaro Mori; Jeffrey Y. W. Mak; David P. Fairlie; Takeshi Bamba; Eri Ishikawa; Masamichi Nagae; Jamie Rossjohn; Sho Yamasaki
• Keywords: Bile Acids and Salts; Minor Histocompatibility Antigens; 0301 basic medicine; Mice; 03 medical and health sciences; Sulfates; Animals; Antigens; Ligands; Mucosal-Associated Invariant T Cells

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.