AbstractThere is significant interest in targeting MAIT cells with immunostimulatory agents to enhance immune responses. Mycobacterium tuberculosis (M. tb.) is a pervasive respiratory disease that could benefit from treatments that augment immunity. Here we investigate the role of MAIT cells in M. tb. infection and the potential for MAIT cell-targeted immunotherapy to control bacterial burdens. We find that MAIT cells fail to substantially accumulate in the lungs during murine pulmonary M. bovis BCG and M. tb. infections but this defect is overcome by intranasal installation of a TLR2/6 agonist and a MAIT cell antigen. Although artificially induced MAIT cells produce important cytokines in both infections, they control BCG but not M. tb. growth in the lungs. Correspondingly, M. tb.-infected mouse macrophages are relatively resistant to MAIT cell antimicrobial activities in vitro. Thus, MAIT cell antigen-mediated immunotherapy for M. tb. presents a complex challenge.