Mucosal-associated Invariant T (MAIT) cells recognise metabolite antigens, including 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), which forms from the riboflavin biosynthesis intermediate 5-amino-6-(ribityl-amino)-uracil (5-A-RU) reacting with glycolysis metabolite methylglyoxal. Riboflavin synthesis is an essential metabolic pathway present in diverse microorganisms, including both bacteria and fungi, providing a target of immune recognition of metabolically active microorganisms. MAIT cells are capable of diverse effector functions; they exist in mice as two main subsets, namely, T-bet-expressing MAIT1 and RORgt-expressing MAIT17 cells. The anti-bacterial protective capacity of MAIT cells has been clearly demonstrated in mouse models of infections, with important roles in tissue repair, cancer and autoimmunity also emerging.
Our studies show the skewed expansion of distinct MAIT cell subsets following infections with different pathogens or via different inoculation routes. For example, intranasal administration of Legionella longbeachae in mice drives a predominantly MAIT17 response in the lungs, whereas systemic Francisella tularensis infection expands MAIT1 cells in several organs. Here, we found that inoculation of mice with Aspergillus fumigatus also results in a significant expansion of MAIT cells, with a predominance of MAIT17 or MAIT1 cells following intranasal or intravenous infection, respectively. The presence of MAIT cells afforded a level of protection compared to MAIT-cell deficient mice.
Despite heavily skewed MAIT cell responses, the relative importance of each MAIT subset in immune protection against various bacterial or fungal pathogens is currently uncertain. We have developed methods to activate and expand MAIT cells in mice using 5-OP-RU or 5-A-RU and co-stimuli, which recapitulate the skewed responses seen in models of infection. We employ these protocols to assess MAIT cell function in different contexts including bacterial and fungal infections and tumour models. Work towards defining and optimising the protective capacity of MAIT cells in these settings will be presented.