Following pathogen invasion, T cells play a crucial role in providing protective immunity. The initial event that causes T cell activation is the recognition of pathogen derived antigen (Ag), presented by major histocompatibility complex (MHC) molecules, via the T cell receptor (TCR). In addition to TCRs, T cells also express co-receptor molecules CD8αβ and CD4 which also engage MHC-I and MHC-II molecules, respectively. Co-receptor engagement can improve T cell sensitivity for antigen and in some cases is critical for T cell activation. In the last two decades, T cells bearing TCRs reactive to lipid and small molecule antigens have been discovered. These include Mucosal-Associated Invariant T (MAIT) cells, which are restricted by the monomorphic MHC-I like molecule MR1.

Using MR1-tetramers we showed that MAIT cell co-receptor expression is discordant with other T cells. MAIT cells predominantly express CD8 or can be co-receptor deficient. Given the high frequency of CD8αα+ and CD8αb+ MAIT cells, we sought to determine whether the CD8 co-receptor could bind to MR1 and influence immune outcomes. Whilst not all MHC-I residues known to bind to CD8 are conserved in MR1, MR1-tetramers mutated at the same positions abrogated CD8 binding, indicating that CD8 binds to MR1 in a fashion similar to MHC-I molecules. Surprisingly, CD8αα was capable of engaging MR1-tetramer independently of a TCR, suggesting that MR1 has a higher affinity for CD8aa as compared to MHC-I molecules. Further, we demonstrated that CD8αα+ and CD8αb+ MAIT cells consistently produced higher amounts of cytokines than the other MAIT cell subsets and that CD8 blockade dramatically decreased cytokine production of these cells.

Our observations suggest that MAIT cells utilize the CD8 co-receptor to engage MR1 and that this interaction enables a robust cytokine response.