MR1 displays the microbial metabolome driving selective MR1-restricted T cell receptor usage

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Science Immunology  13 Jul 2018:
Vol. 3, Issue 25, eaao2556
DOI: 10.1126/sciimmunol.aao2556

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A broader repertoire

A subset of T cells can present microbial ligands using MR1, a nonconventional MHC molecule. MR1 is known to present metabolites from microbes like Mycobacterium tuberculosis, but the breadth of the MR1 ligandome is not well understood. Harriff et al. use mass spectrometry and molecular networking to identify MR1-presented ligands from two divergent microbes, Escherichia coli and Mycobacterium smegmatis. They observed that MR1 can present a surprisingly broad array of ligands for both microbes, and ligands can be distinguished by different TCRs on MR1-restricted T cells and can have inhibitory or activating effects. These data broaden the understanding of MR1 as a critical molecule for presenting microbial ligands to the immune system.


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., Mycobacterium tuberculosis, Streptococcus pyogenes, and Francisella tularensis) and enteric pathogens (e.g., Escherichia coli and Salmonella 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 E. coli and Mycobacterium smegmatis. We found that the MR1 ligandome is unexpectedly broad, revealing functionally distinct ligands derived from E. coli and M. smegmatis. 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.

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