MAIT cells protect against pulmonary Legionella longbeachae infection

Abstract

Mucosal associated invariant T (MAIT) cells recognise conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in antibacterial host defence, yet their functions in protection against clinically important pathogens are unknown. Here we show that mouse Legionella longbeachae infection induces MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in immunocompetent host animals. MAIT cell protection is more evident in mice lacking CD4+ cells, and adoptive transfer of MAIT cells rescues immunodeficient Rag2−/−γC−/− mice from lethal Legionella infection. Protection is dependent on MR1, IFN-γ and GM-CSF, but not IL-17A, TNF or perforin, and enhanced protection is detected earlier after infection of mice antigen-primed to boost MAIT cell numbers before infection. Our findings define a function for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity.

MAIT cells as attractive vaccine targets

“…The bacterial load was significantly lower in wild‐type mice that had been previously exposed to 5‐OP‐RU. This is the first encouraging example of actually examining 5‐OP‐RU to serve as a vaccine .…”

Characterization and Purification of Mouse Mucosal‐Associated Invariant T (MAIT) Cells

“…These are now produced by the NIH Tetramer Core Facility and are permitted to be distributed by the University of Melbourne. The tetramer technology in combination with recently established infection models (Rahimpour et al., ; Wang et al., ) makes it possible to expand and characterize MAIT cells with precision. This unit describes practical step‐by‐step protocols and should provide a technical platform for the MAIT cell research community.…”

“…If the recipients (Support Protocol 5) are RAG2 − / − γC − / − mice, any transferred T cells, including MAIT cells, will spontaneously expand (known as homeostatic proliferation). We have observed that a few contaminating non‐MAIT T cells (<1%) could account for up to 10% to 15% of all transferred T cells after 2 weeks, suggesting different rates of proliferation (Wang et al., ). This will impact the recipients’ immune capacity and may produce unexpected results.…”

“…Specifically, the MAIT cell antigen 5‐(2‐oxopropylideneamino)‐6‐ D ‐ribitylaminouracil (5‐OP‐RU) is formed from the vitamin B2 (riboflavin) biosynthesis precursor 5‐amino‐6‐ D ‐ribitylaminouracil (5‐A‐RU) and the small cellular metabolite methylglyoxal (Corbett et al., ; Kjer‐Nielsen et al., ). Riboflavin synthesis is an essential metabolic pathway in many microbes, including bacteria and fungi, so MAIT cells play a protective role in the clearance of at least some infections (D'Souza, Chen, & Corbett, ; Meierovics, Yankelevich, & Cowley, ; Wang et al., ). MAIT cells are present in most mammals and reside in mucosal and other tissues as well as in the circulation (Boudinot et al., ; Treiner et al., ).…”

“…This can be used in conjunction with staining for other surface phenotypic markers or for intracellular cytokines or transcription factors (TFs; Alternate Protocol 1). To increase MAIT cell yields, infection with the bacterial pathogen Legionella longbeachae (Wang et al., ) or Salmonella enterica Typhimurium (Chen et al., ; Basic Protocol 2) or an immunization scheme [Toll‐like receptor (TLR) agonist plus the MAIT cell antigen 5‐OP‐RU; Alternate Protocol 2] can be used to first expand MAIT cells to large numbers (Chen et al., ; D'Souza, Pediongco, et al., ; Wang et al., ). The MAIT cells can then be functionally examined or sorted for adoptive transfer (Support Protocol 5), after which the cells are further studied in the recipient mice.…”