A first indication of the biological role of mucosal associated invariant T (MAIT) cells reveals that this discrete T cell subset is broadly reactive to bacterial infection. In particular MAIT cells recognize Mycobacterium tuberculosis-infected lung airway epithelial cells via the most evolutionarily conserved major histocompatibility molecule.
MR1-restricted T cells (MR1Ts) are a T cell subset that recognize and mediate host defense to a broad array of microbial pathogens, including respiratory pathogens (e.g., ,, ) and enteric pathogens (e.g., and species). Mucosal-associated invariant T (MAIT) cells, a subset of MR1Ts, were historically defined by the use of a semi-invariant T cell receptor (TCR) and recognition of small molecules derived from the riboflavin biosynthesis pathway presented on MR1. We used mass spectrometry to identify the repertoire of ligands presented by MR1 from the microbes and We found that the MR1 ligandome is unexpectedly broad, revealing functionally distinct ligands derived from and The identification, synthesis, and functional analysis of mycobacterial ligands reveal that MR1T ligands can be distinguished by MR1Ts with diverse TCR usage. These data demonstrate that MR1 can serve as an immune sensor of the microbial ligandome.
Studies on mucosal-associated invariant T cells (MAITs) in nonhuman primates (NHP), a physiologically relevant model of human immunity, are handicapped due to a lack of macaque MAIT-specific reagents. Here we show that while MR1 ligand-contact residues are conserved between human and multiple NHP species, three T cell receptor (TCR) contact residue mutations in NHP MR1 diminish binding of human MR1 tetramers to macaque MAITs. Construction of naturally loaded macaque MR1 tetramers facilitated identification and characterization of macaque MR1-binding ligands and MAITs, both of which mirrored their human counterparts. Using the macaque MR1 tetramer we show that NHP MAITs activated in vivo in response to both BCG vaccination and M. tuberculosis infection. These results demonstrate that NHP and human MR1 and MAITs function analogously, and establish a preclinical animal model to test MAIT-targeted vaccines and therapeutics for human infectious and autoimmune disease.
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