Résumé
Mucosal-associated invariant T (MAIT) cells are an effector population of innate-like T cells that comprise up to 5% of T cells within human lungs. Rather than recognizing peptides like conventional T cells, MAIT cells utilize their semi-invariant T cell receptors to identify small molecules, such as intermediates of riboflavin synthesis, presented by MHC-class 1 related protein (MR1). Because this biosynthetic pathway is highly conserved among bacteria and fungi, MAIT cells promote immunity to a wide array of pulmonary pathogens, such as Legionella and Francisella species. However, due to the low level of MR1 expression in several major cell lineages, the populations that present microbial metabolites to MAIT cells during infection remain unknown, preventing optimization of MAIT cell vaccines. Utilizing the F. tularensis live vaccine strain to induce pneumonic tularemia, we find that MAIT cells are the predominant effector T cell population, accounting for more than 20% of IFN-γ producing T cells. Infection of MR1f/f conditional knockout mice following broad deletion of MR1 with the tamoxifen-inducible Rosa26-creERT2 allele revealed that MR1-mediated presentation is necessary for the MAIT cell response to F. tularensis. Use of MR1f/f strains that express Cre recombinase under control of cell-specific promoters has allowed us to determine the relative contributions towards MAIT cell activation from dendritic cells, macrophages, and neutrophils. This work defines the antigen presenting cells that are critical for MAIT cell activation during an intracellular bacterial infection and identifies cellular targets to enhance MAIT cell responses. Supported by NIAID grants K22 AI146217 and R21 AI171697