Editors' ChoiceImmunology

Antigenic Metabolites

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Science Signaling  20 May 2014:
Vol. 7, Issue 326, pp. ec135
DOI: 10.1126/scisignal.2005496

To discriminate between pathogens and host, T cells rely on the presentation of molecules, mostly peptides, lipids, and sugars, that are chemically unique to the pathogen. Corbett et al. add to this list of antigenic molecules by identifying molecules derived from precursors of riboflavin that interact with products of glycolytic metabolism. Mass spectrometry and structural analysis indicated that these molecules bound to MR1, the protein that activates a specific type of T cell, mucosal-associated invariant T (MAIT) cells. Supernatant from bacteria lacking the enzymes required to synthesize riboflavin failed to stimulate a Jurkat cell line engineered to have a T cell receptor from MAIT cells. Supernatant from bacteria with loss-of-function of enzymes upstream of, but not those downstream from, the production of the riboflavin precursor 5-amino-6--ribtylaminouracil (5-A-RU) indicated that 5-A-RU was essential to the formation of the antigens. Chemical synthesis studies showed that the antigens bound to MR1 could form spontaneously through nonenzymatic reactions of glyoxal or methylglyoxal (also known as pyruvaldehyde) with 5-A-RU. Structural analysis revealed that in vitro unfolded MR1 could be refolded correctly in the presence of 5-A-RU and either glyoxal or methylglyoxal, but not in the presence of 5-A-RU alone. MR1 bound to either of the 5-A-RU adducts activated human MAIT cells in samples of peripheral blood mononuclear cells. Thus, the immune system can recognize and stabilize transiently formed chemical intermediates resulting from nonenzymatic reactions between a molecule specifically produced by bacteria and common products of metabolism.

A. J. Corbett, S. B. Eckle, R. W. Birkinshaw, L. Liu, O. Patel, J. Mahony, Z. Chen, R. Reantragoon, B. Meehan, H. Cao, N. A. Williamson, R. A. Strugnell, D. Van Sinderen, J. Y. Mak, D. P. Fairlie, L. Kjer-Nielsen, J. Rossjohn, J. McCluskey, T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature. 509, 361–365 (2014). [PubMed]