CD8 coreceptor engagement of MR1 enhances antigen responsiveness by human MAIT and other MR1-reactive T cells

Souter et al. demonstrate that CD8 binds MR1 and that the CD8-MR1 interaction enhances MAIT cell antigen recognition and associated functional responses. They also show that the CD8-MR1 interaction is critical for the recognition of MR1 presenting folate-derived antigens by other MR1-reactive T cells. Mucosal-associated invariant T (MAIT) cells detect microbial infection via recognition of riboflavin-based antigens presented by the major histocompatibility complex class I (MHC-I)-related protein 1 (MR1). Most MAIT cells in human peripheral blood express CD8 alpha alpha or CD8 alpha beta coreceptors, and the binding site for CD8 on MHC-I molecules is relatively conserved in MR1. Yet, there is no direct evidence of CD8 interacting with MR1 or the functional consequences thereof. Similarly, the role of CD8 alpha alpha in lymphocyte function remains ill-defined. Here, using newly developed MR1 tetramers, mutated at the CD8 binding site, and by determining the crystal structure of MR1-CD8 alpha alpha, we show that CD8 engaged MR1, analogous to how it engages MHC-I molecules. CD8 alpha alpha and CD8 alpha beta enhanced MR1 binding and cytokine production by MAIT cells. Moreover, the CD8-MR1 interaction was critical for the recognition of folate-derived antigens by other MR1-reactive T cells. Together, our findings suggest that both CD8 alpha alpha and CD8 alpha beta act as functional coreceptors for MAIT and other MR1-reactive T cells.