Antigen presentation plays a critical role in generating T cell responses for immunity. Major histocompatibility complex class I-related protein 1 (MR1) is an evolutionarily conserved but poorly understood antigen-presenting molecule, which captures and displays small metabolites from a diverse array of microbes to Mucosal-Associated Invariant T (MAIT) cells to induce protective immunity. The mechanisms involved in MR1 antigen presentation are well characterized, but the identity of the cells presenting antigens to MAIT cells remain unclear. Using a MR1-reporter model, we previously found that MR1 is predominantly expressed by macrophages under healthy state. Here, we use a murine model of Staphylococcus aureus peritonitis to describe the dynamics of MR1 presentation and MAIT cell activation by macrophages during infection.
We found that MR1 transcription and protein expression decreased to undetectable levels in macrophages at 1 day post-infection (DPI) and did not return to baseline levels until 21 DPI. Accordingly, the in vitro antigen presentation capacity of macrophages was also defective at 1 DPI. Interestingly, none of peritoneal cell population upregulated MR1 during infection. To assess the dynamics of MR1-dependent MAIT cell activation during infection, we measured Nur77 expression, a marker of T cell receptor stimulation. We observed increased Nur77 expression 3 hours after S. aureus inoculation followed by a return to baseline level at 24h. MAIT cells expanded in infected mice and contributed to control infection because the bacterial burden was higher in MR1-deficient mice.
Our findings imply that tissue macrophages are equipped with a pool of MR1 that rapidly present bacterial antigens and activate MAIT cells during early infection. The rapid subsequent loss of MR1 expression in macrophages may serve to prevent tissue pathology by chronic stimulation of MAIT cells. These findings may enable to develop immunotherapeutic strategies that harness the powerful but temporary ability of macrophages to recruit MAIT cells.