MR1 presents metabolite antigens, produced by a broad range of bacteria and yeast, to innate-like MAIT cells enriched in barrier tissues. This activates MAIT cells to recruit the adaptive immune response, resolve microbial infections and enact tissue repair. Thus, MR1 is a critical point of interaction between the immune system and microbes. We have a gained a good understanding of the molecules and intracellular mechanisms involved in metabolite MR1 presentation, but the cells that perform this activity in vivo to regulate MAIT cell effector functions are not known.
We have generated a novel mouse model that reveals the expression of MR1 by a fluorescent reporter protein. Macrophages resident in tissues such as the lungs, and in peritoneal and pleural cavities expressed high levels of MR1, while those from the spleen and gut did not. This was confirmed by gene-expression and antigen presentation studies and corroborated in humans, where lung macrophages also express the highest MR1 levels compared to other lung or blood cells. A macrophage-specific MR1 knock out mouse strain (MΦ-ΜR1ΚΟ) had normal numbers of MAIT cells in steady-state conditions. However, MAIT cell activation and expansion was defective in MΦ-ΜR1ΚΟ mice following pulmonary infection by two bacterial pathogens. Intriguingly, healthy MΦ-ΜR1ΚΟ mice carried an altered respiratory microbiome compared to their wild-type littermates. These findings demonstrate that tissue macrophages are key MR1-presenting cells and mediate (i) crosstalk between the immune system and commensals to shape the microbiota; and (ii) MAIT cell simulation and immunity during microbial infection.
Our results highlight the specialised role of macrophages in MR1 presentation of microbial ligands. Future work will address whether macrophages are also required for anti-cancer immunity by MAIT and other types of MR1T cells.