The balance of interleukin-12 and interleukin-23 determines the bias of MAIT1 versus MAIT17 responses during bacterial infection.

Mucosal-associated invariant T (MAIT) cells are a major subset of innate-like T cells mediating protection against bacterial infection through recognition of microbial metabolites derived from riboflavin biosynthesis. Mouse MAIT cells egress from the thymus as two main subpopulations with distinct functions, namely, T-bet-expressing MAIT1 and RORγt-expressing MAIT17 cells. Previously, we reported that inducible T-cell costimulator and interleukin (IL)-23 provide essential signals for optimal MHC-related protein 1 (MR1)-dependent activation and expansion of MAIT17 cells in vivo. Here, in a model of tularemia, in which MAIT1 responses predominate, we demonstrate that IL-12 and IL-23 promote MAIT1 cell expansion during acute infection and that IL-12 is indispensable for MAIT1 phenotype and function. Furthermore, we showed that the bias toward MAIT1 or MAIT17 responses we observed during different bacterial infections was determined and modulated by the balance between IL-12 and IL-23 and that these responses could be recapitulated by cytokine coadministration with antigen. Our results indicate a potential for tailored immunotherapeutic interventions via MAIT cell manipulation.

An overview on the identification of MAIT cell antigens.

Mucosal associated invariant T (MAIT) cells are restricted by the monomorphic MHC class I-like molecule, MHC-related protein-1 (MR1). Until 2012, the origin of the MAIT cell antigens (Ags) was unknown, although it was established that MAIT cells could be activated by a broad range of bacteria and yeasts, possibly suggesting a conserved Ag. Using a combination of protein chemistry, mass spectrometry, cellular biology, structural biology and small molecule chemistry, we discovered MR1 ligands derived from folic acid (vitamin B9) and from an intermediate in the microbial biosynthesis of riboflavin (vitamin B2). While the folate derivative 6-formylpterin generally inhibited MAIT cell activation, two riboflavin pathway derivatives, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil and 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil, were potent MAIT cell agonists. Other intermediates and derivatives of riboflavin synthesis displayed weak or no MAIT cell activation. Collectively, these studies revealed that in addition to peptide and lipid-based Ags, small molecule natural product metabolites are also ligands that can activate T cells expressing αß T-cell receptors, and here we recount this discovery.

Human blood MAIT cell subsets defined using MR1 tetramers.

Mucosal-associated invariant T (MAIT) cells represent up to 10% of circulating human T cells. They are usually defined using combinations of non-lineage-specific (surrogate) markers such as anti-TRAV1-2, CD161, IL-18Rα and CD26. The development of MR1-Ag tetramers now permits the specific identification of MAIT cells based on T-cell receptor specificity. Here, we compare these approaches for identifying MAIT cells and show that surrogate markers are not always accurate in identifying these cells, particularly the CD4+ fraction. Moreover, while all MAIT cell subsets produced comparable levels of IFNγ, TNF and IL-17A, the CD4+ population produced more IL-2 than the other subsets. In a human ontogeny study, we show that the frequencies of most MR1 tetramer+ MAIT cells, with the exception of CD4+ MAIT cells, increased from birth to about 25 years of age and declined thereafter. We also demonstrate a positive association between the frequency of MAIT cells and other unconventional T cells including Natural Killer T (NKT) cells and Vδ2+ γδ T cells. Accordingly, this study demonstrates that MAIT cells are phenotypically and functionally diverse, that surrogate markers may not reliably identify all of these cells, and that their numbers are regulated in an age-dependent manner and correlate with NKT and Vδ2+ γδ T cells.