Mucosal associated invariant T-cells (MAIT cells) are an abundant population of innate-like human T cells in the blood, liver and gut mucosa.1 Their activation upon presentation of bacterially derived antigens by an MHC class-I related molecule (MR1) has been implicated in pathological processes such as inflammatory bowel disease2 and the immune response to pulmonary bacterial infection3. Although the identity of the antigen(s) had been elusive, we recently discovered that an unstable riboflavin-type metabolite binds to MR1 and then activates MAIT cells.1,4 It is formed in vivo via the condensation of 5-amino-6-D-ribitylaminouracil (5-A-RU, 1), a key bacterial riboflavin biosynthetic intermediate, and pyruvaldehyde (2), a metabolite of glycolysis. Through chemical synthesis and characterization by MS and NMR, the solution structure of this unstable antigen was determined unambiguously as 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OP-RU, 3), which readily undergoes degradative cyclization to give lumazine 4. The MAIT TCR-MR1-antigen crystal structure revealed the formation of a Schiff base between MR1 Lys43 and 5-OP-RU stabilizing the antigen. Together, these show an unexpected mechanism of generating T-cell antigens by using disparate chemicals from different metabolic pathways. (1) Kjer-Nielsen, L. et al. Nature 2012, 491, 717. (2) Serriari, N. E.; Eoche, M.; Lamotte, L.; Lion, J.; Fumery, M.; Marcelo, P.; Chatelain, D.; Barre, A.; Nguyen-Khac, E.; Lantz, O.; Dupas, J. L.; Treiner, E. Clin. Exp. Immunol. 2014, 176, 266. (3) Meierovics, A.; Yankelevich, W. J.; Cowley, S. C. Proc. Natl. Acad. Sci. 2013, 110, E3119. (4) Corbett, A. J.; Eckle, S. B. G.; Birkinshaw, R. W.; Liu, L.; Patel, O.; Mahony, J.; Chen, Z.; Reantragoon, R.; Meehan, B.; Cao, H.; Williamson, N. A.; Strugnell, R. A.; Van Sinderen, D.; Mak, J. Y. W.; Fairlie, D. P.; Kjer-Nielsen, L.; Rossjohn, J.; McCluskey, J. Nature 2014, 509, 361.

T-cell antigen formed from distinct metabolic pathways

250th National Meeting (2015)

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