T Cell Activation by Transitory Neo-Antigens Derived from Distinct Microbial Pathways

Corbett AJ, Eckle SB, Birkinshaw RW, Liu L, Patel O, Mahony J, Chen Z, Reantragoon R, Meehan B, Cao H, Williamson NA, Strugnell RA, Van Sinderen D, Mak JY, Fairlie DP, Kjer-Nielsen L, Rossjohn J, McCluskey J.

Nature. 2014 May 15;509(7500):361-5. doi: 10.1038/nature13160. Epub 2014 Apr 2.

From left to right: Browyn Meehan, Nicholas Williamson, Jamie Rossjohn, Richard Birkinshaw, Alexandra Corbett, James McCluskey, Zhenjun Chen, Richard Strugnell and Hanwei Cao

From left to right: Browyn Meehan, Nicholas Williamson, Jamie Rossjohn, Richard Birkinshaw, Alexandra Corbett, James McCluskey, Zhenjun Chen, Richard Strugnell and Hanwei Cao

This study used bacterial riboflavin mutants to pinpoint the origin of Mucosal Associated Invariant T (MAIT) cell-activating antigens to 5-amino-6-d-ribitylaminouracil (5-A-RU), an intermediate in microbial riboflavin synthesis. This riboflavin precursor combines with small metabolites glyoxal and methylglyoxal, forming simple adducts 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU). These unstable reaction intermediates can be captured and stabilized by MR1 and presented to MAIT cells as shown by crystal structures of MAIT TCR ternary complexes. Importantly, humans and other mammals use, but do not make riboflavin; only bacteria and fungi do. Mass spectra identified 5-OP-RU and 5-OE-RU captured by MR1 from bacterial cultures that activate MAIT cells, but not from non-activating bacteria, showing that these MAIT antigens are present in a range of microbes. Thus, MAIT cells act as immune surveillance for metabolically active microbes. That makes our MAITs a useful guard against infection in our gut, mouth and lungs. Knowledge of how MAIT antigens are formed has allowed development of MR1 tetramer reagents to specifically identify and study MAIT cells in humans and mice. PubMed:24695216