Targeting MAIT cells by vaccination with S. enterica serotype Typhimurium to prevent lung infections

Abstract

Abstract Nearly all currently licensed vaccines elicit antibody responses to induce long-lasting immunity. For intracellular pathogens, to some extent out of reach for antibodies, protective vaccination will require not just antibody production, but also T cell-mediated responses. Mucosal Associated Invariant T (MAIT) cells recognize microbial vitamin B metabolites presented by the MHC-I-like molecule, MR1, via a semi-invariant TCR. These innate-like T cells are present at low levels in mice in mucosal tissues, especially the lung, as well as other sites such as blood, liver and spleen. Previous studies have demonstrated that Salmonella enterica serotype Typhimurium potently expands long-lived MAIT cells to nearly 40% of lung αβ T cells. Using this model, we determined that expansion of MAIT cells requires infection with intracellular bacteria, as an invasion mutant of S. enterica does not induce MAIT cell expansion. Following treatment with an attenuated strain of S. enterica, MAIT cells expand into short-term effector memory (CD127−KLRG1+) and memory precursor (CD127+KLRG1−) populations that differ in cytokine, transcription factor, and metabolic profiles. Following adoptive transfer, CD127+ MAIT cells, but not KLRG1+ cells, protect mice from infection with a different bacterium, Streptococcus pneumoniae, a leading cause of pneumonia and other diseases. Further, vaccination with S. enterica limits S. pneumoniae-induced mortality in mice. These studies demonstrate that some intracellular bacteria induce distinct, long-lived MAIT cell populations, and that these cells are a promising target for vaccines against lung pathogens.