MAIT cells can respond to MR1 and microbially-derived ligand via their TCR. They can also be readily activated in a TCR-independent manner, through sensing of inflammatory cues. This behaviour potentially broadens their involvement in host defence and inflammation. We have previously explored this and shown that in humans, MAIT cells (and related cell types) are readily activated in vivo in response to diverse virus infections via cytokines including IL-18 and Type I interferon. In subsequent studies, my group have collaborated with James McCluskey’s team working with murine MAIT cells and have now addressed whether such viral sensing has any protective or pathogenic role in vivo. In this talk I will describe some of the key findings regarding activation and protection using intact C57BL/6, knockout and transfer models. Since MAIT cells are highly abundant in humans, and since they are readily activated by a variety of significant viral pathogens, such proof-of-principle is important in understanding their role in disease. This non-TCR dependent behaviour may also be relevant in bacterial infections, even for pathogens with an intact riboflavin synthesis pathway.