Major histocompatibility complex class I-related protein 1 (MR1) is a monomorphic antigen-presenting molecule highly conserved across mammals. It presents vitamin B-related metabolite antigens, produced by a broad range of bacteria and yeast, to mucosal-associated invariant T (MAIT) cells. This activates MAIT cells to resolve microbial infections and enact tissue repair to maintain homeostasis. Thus, MR1 is a critical point of interaction between the immune system and commensal or pathogenic microbes.
MR1-expressing cells represent therapeutic targets to modulate the MR1-MAIT cell axis. However, unlike other antigen presenting molecules, MR1 is expressed at very low levels and is difficult to detect by conventional methods. This significantly hampers research in this field, and thus the cells that express MR1 in vivo and activate MAIT cells are not known.
To address this knowledge gap, we generated a novel mouse model that reveals the expression of MR1 by a fluorescent reporter protein. After confirming that the fluorescence level accurately reports on MR1 protein levels in wild-type mice, we have begun a systematic map of MR1-expressing cells in vivo. Macrophages resident in tissues such as the lung and peritoneal cavity expressed high levels of MR1, while those from the spleen and gut did not. Further, classical antigen presenting cells such as dendritic cells and B cells expressed low amounts. We found that the MR1-low bone marrow precursors expressed MR1 upon differentiating to lung or peritoneal macrophages, indicating the tissue location drives expression. Finally, using two models of bacterial infection we find MR1 expression was strongly downregulated in macrophages, and infiltrating cells did not express MR1.
Together, these findings suggest that some macrophages are key MR1-expressing cells in vivo. We hypothesise that these innate presenting cells are already equipped with MR1 prior to infection, enabling them to rapidly activate MAIT cells upon microbial encounter.