Efficient 5-OP-RU-Induced Enrichment of Mucosa-Associated Invariant T Cells in the Murine Lung Does Not Enhance Control of Aerosol Mycobacterium tuberculosis Infection

Abstract

Mucosa-associated invariant T (MAIT) cells are an innate-like T cell subset in mammals that recognize microbial vitamin B metabolites presented by the evolutionarily conserved major histocompatibility complex class I (MHC I)-related molecule, MR1. Emerging data suggest that MAIT cells may be an attractive target for vaccine-induced protection against bacterial infections because of their rapid cytotoxic responses at mucosal services to a widely conserved bacterial ligand. In this study, we tested whether a MAIT cell priming strategy could protect against aerosol <i>Mycobacterium tuberculosis</i> infection in mice. Intranasal costimulation with the lipopeptide Toll-like receptor (TLR)2/6 agonist, Pam2Cys (P2C), and the synthetic MR1 ligand, 5-OP-RU, resulted in robust expansion of MAIT cells in the lung. Although MAIT cell priming significantly enhanced MAIT cell activation and expansion early after <i>M. tuberculosis</i> challenge, these MAIT cells did not restrict <i>M. tuberculosis</i> bacterial load. MAIT cells were depleted by the onset of the adaptive immune response, with decreased detection of granzyme B⁺ and gamma interferon (IFN-γ)⁺ MAIT cells relative to that in uninfected P2C/5-OP-RU-treated mice. Decreasing the infectious inoculum, varying the time between priming and aerosol infection, and testing MAIT cell priming in nitric oxide synthase 2 (NOS2)-deficient mice all failed to reveal an effect of P2C/5-OP-RU-induced MAIT cells on <i>M. tuberculosis</i> control. We conclude that intranasal MAIT cell priming in mice induces early MAIT cell activation and expansion after <i>M. tuberculosis</i> exposure, without attenuating <i>M. tuberculosis</i> growth, suggesting that MAIT cell enrichment in the lung is not sufficient to control <i>M. tuberculosis</i> infection.