Establishment of an MR1 Presentation Reporter Screening System and Identification of Phenylpropanoid Derivatives as MR1 Ligands

Mucosal-associated
invariant T (MAIT) cells are innate-like T cells
that are modulated by ligands presented on MHC class I-related proteins
(MR1). These cells have attracted attention as potential drug targets
because of their involvement in the initial response to infection
and various disorders. Herein, we have established the MR1 presentation
reporter assay system employing split-luciferase, which enables the
efficient exploration of MR1 ligands. Using our screening system,
we identified phenylpropanoid derivatives as MR1 ligands, including
coniferyl aldehyde, which have an ability to inhibit the MR1–MAIT
cell axis. Further, the structure–activity relationship study
of coniferyl aldehyde analogs revealed the key structural features
of ligands required for MR1 recognition. These results will contribute
to identifying a broad range of endogenous and exogenous MR1 ligands
and to developing novel MAIT cell modulators.