Vitamin B2 (riboflavin) is essential for metabolic functions and is synthesized by many bacteria, yeast, and plants, but not by mammals and other animals, which must acquire it from the diet. In mammals, modified pyrimidine intermediates from the microbial biosynthesis of riboflavin are recognized as signature biomarkers of microbial infection. This recognition occurs by specialized lymphocytes known as mucosal associated invariant T (MAIT) cells. The major histocompatibility class I-like antigen-presenting molecule, MR1, captures these pyrimidine intermediates, but only after their condensation with small molecules derived from glycolysis and other metabolic pathways to form short-lived antigens. The resulting MR1-Ag complexes are recognized by MAIT cell antigen receptors (␣ T cell receptors (TCRs)), and the subsequent MAIT cell immune responses are thought to protect the host from pathogens at mucosal surfaces. Here, we review our understanding of how these novel antigens are generated and discuss their interactions with MR1 and MAIT TCRs.
MAIT CellsT cells are lymphocytes that mediate a range of immune functions such as killing infected host cells and producing cytokines and other factors that regulate immunity and inflammation. T cells generally recognize peptide antigens (Ags) 6 or lipid-based Ags complexed to specialized Ag-presenting molecules, MHC and CD1, respectively, that interact with an Agspecific ␣ T cell receptor (TCR) (1, 2). An expansive repertoire of TCRs is generated by the random rearrangement of V, D, and J gene segments and by pairing of TCR ␣-and -chains, allowing specific recognition of a diverse range of Ags. Mucosal associated invariant T (MAIT) cells are a specialized subset of ␣ T cells originally identified in CD4 Ϫ CD8 Ϫ (double negative) human blood lymphocytes expressing a dominant invariant TCR ␣-chain gene rearrangement, TRAV1-2-TRAJ33 (based on IMGT, or V␣7.2-J␣33 based on Arden nomenclature (3)) (4, 5) with less frequent usage of TRAJ12 and TRAJ20 (6 -9). The MAIT TCR ␣-chain contains a complementarity-determining region (CDR) 3 loop of constant length with two variable amino acids in the V-J junction (4) located at the base of this loop (10, 11). MAIT cells are evolutionarily conserved in mammals with the canonical TCR ␣-chain composed of homologous TRAV and TRAJ elements also found in mice, cattle (5) and sheep (12). TRAV1-2 is not exclusive to MAIT cells, with some MHC-Irestricted T cells (13,14) and CD1b-restricted germline-encoded, mycolyl lipid-reactive (GEM) T cells also using this TRAV gene segment (15).The -chain of MAIT cells has no apparent restrictions in J usage, but there is a bias toward the use of human TRBV20 and TRBV6 segments (or V2 and V13 based on Arden nomenclature) and, similarly in mice, to TRBV19 and TRBV13 (or V6 and V8 based on Arden nomenclature), both being the murine orthologous segments of human TRBV6 (4, 5, 9). Furthermore, recent TCR sequencing revealed a marked oligoclonality of MAIT TCR CDR3 regions and a bias in the length of most...