Recent studies of mucosal-associated invariant T (MAIT) cells indicate that they respond to a range of pathogen-derived vitamin metabolites presented at the cell surface by the evolutionarily conserved and nonpolymorphic MHC-related class I-like molecule, MR1. Two papers in this issue describe how the structure of the T cell receptors (TCRs) of MAIT cells adapts to recognize metabolites from different intracellular infections.
Unlike classical αβ T cells, which recognize a broad range of peptide antigens in complex with polymorphic MHC class I or MHC class II molecules, nonclassical T cells have a more restricted repertoire, recognizing nonpeptide antigens presented by nonpolymorphic MHC class I-like molecules. These nonclassical T cells include NKT cells that detect glycolipid antigens presented by CD1d, germline-encoded mycolyl-lipid reactive (GEM) T cells that recognize CD1b, and the MAIT cells that are the subject of these papers.
To date, MAIT cells have been considered to be innate cells in that they recognize a limited number of conserved antigens in the context of the nonpolymorphic MR1 molecule. Gold et al. characterized the TCR repertoire of MAIT cells reactive with an epithelial cell line infected with either M. smegmatis, S. typhimurium, or C. albicans. Although the use of Vα genes was restricted, Vβ usage was more varied, reflecting differences in the organisms to which the particular MAIT TCR responded. This suggests that MAIT cells have adaptive capacity within a pattern-like recognition system.
Eckle et al., in a technological tour de force, report the crystallographic structures, biophysical properties, and functional recognition of MAIT TCRs, as well as ternary structures of MAIT TCRs bound to MR1-antagonist or MR1-agonist vitamin B–derived antigens. They show that different TCRs bind the same MR1–antigen complexes slightly differently, with different affinities and with structural accommodations including a general preservation of TCR docking mode on the MR1, conserved interaction of a key TCR α-chain CDR3-encoded residue (Tyr95α) with the antigen, and significant interactions of the hypervariable CDR3β loop with the antigen. The characterization of a strong antagonist of MAIT TCR recognition reveals plasticity of the MR1 binding pocket to accommodate the ligand and shows how the ligand itself can affect MR1 stability.
Collectively, these structures indicate that although the conserved TCR Vα-chain plays a major role in MR1 interaction, it also contributes to recognition of stimulatory antigens, whereas Vβ differences may accommodate subtle differences among distinct antigens. These studies support the view that MAIT cells co-evolved with their MR1-presenting element to recognize metabolic products from distinct intracellular microorganisms, conserving the Vα and Jα much like innate pattern recognition receptors, but allowing the Vβ-chains to vary according to the particular pathogen, following the scheme of adaptive immunity.
So, MAIT cells seem to be an “in-between” type of T cell with semi-invariant TCRs, recognizing antigens (at least those we now know) derived from metabolic products of lower organisms, and utilizing conserved, invariant presentation molecules. However, the questions that remain are provocative. How varied are the MR1-presented antigens? How do the metabolite-derived antigens load onto MR1 molecules, and how do they cross organelle barriers from the intracellular sites of infection? Are there self-antigens that mimic the vitamin metabolites for MR1 binding and MAIT cell selection? Can we find ancestral invariant TCR-like molecules that bind MR1-like predecessors that still respond to metabolite antigens?
Although many questions remain, these papers not only enhance our understanding of the evolution and function of MAIT cells and their novel TCRs, but also provide a new perspective on the many immunological solutions that nature has developed to combat pathogens.