Avoidance of MAIT cells is an essential determinant of Listeriamonocytogenes pathogenesis

Abstract

Mucosal-associated invariant T (MAIT) cells are among the most conserved and abundant innate-like T cells in humans that recognize microbial-derived riboflavin precursors and elicit potent antimicrobial responses. The foodborne pathogen Listeria monocytogenes is a broad host-range facultative intracellular pathogen that lacks the riboflavin biosynthetic pathway, leading us to hypothesize that this deficiency is pathoadaptive and allows the pathogen to evade MAIT cells. Here, we show that L. monocytogenes strains engineered to produce riboflavin (L. monocytogenes-ribDEAHT) are attenuated in wild-type mice but fully virulent in MAIT cell-deficient mice. Infection with L. monocytogenes-ribDEAHT prompted rapid and robust MAIT cell expansion in multiple tissues and required the cytolytic effector perforin to eliminate infected cells in vivo and in vitro. We also assessed the therapeutic potential of L. monocytogenes-ribDEAHT-stimulated MAIT cells in both infectious disease and cancer mouse models. Therapeutic administration of L. monocytogenes-ribDEAHT provided protection against Francisella tularensis in the lungs and inhibited tumor growth even in the absence of CD8+ T cells. These findings reveal the importance of MAIT cell evasion during L. monocytogenes infection and highlight the therapeutic potential of engineered L. monocytogenes to activate and harness MAIT cells for protection against infectious disease and cancer. Significance StatementListeria monocytogenes is a bacterial pathogen that grows freely in the environment but can become intracellular following ingestion of contaminated food. Although L. monocytogenes can synthesize most metabolites required for growth, it lacks the genes necessary to produce riboflavin (vitamin B2), an essential cofactor across all domains of life. We hypothesized that lacking riboflavin biosynthesis allows L. monocytogenes to evade mucosal-associated invariant T cells (MAIT cells), which generate potent antimicrobial responses against riboflavin-producing microbes. By engineering L. monocytogenes to produce riboflavin, we show that these strains robustly activate MAIT cells and are highly attenuated in wild-type mice, but not in MAIT cell-deficient mice. Furthermore, MAIT cells activated by engineered L. monocytogenes provided therapeutic protection against other riboflavin-producing bacteria and cancer.