Specific identification, tracking and harnessing of Mucosal Associated Invariant T (MAIT) cells in health and disease — ASN Events
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Specific identification, tracking and harnessing of Mucosal Associated Invariant T (MAIT) cells in health and disease (#4)

Jim McCluskey 1
  1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3000, Australia.

Mucosal associated invariant T (MAIT) cells recognize conserved microbial metabolites from riboflavin synthesis. Their striking evolutionary conservation and relative abundance, implicate them in antibacterial host defense.  Yet their role in protection against clinically significant pathogens, and as potential vaccine targets, remain unknown. The development of Ag-specific MR1-tetramers has allowed more specific tracking and phenotyping of MAIT cells, facilitating their biological characterisation and exploration of translational opportunities.

We have investigated MAIT cell function in two infectious disease models. Firstly, we noted that  following lung infection with Salmonella typhimurium, MAIT cells were rapidly enriched in the lungs of C57BL/6 mice and displayed an activated/memory phenotype. The majority of cells produced interleukin-17 while smaller subsets produced interferon-g or tumor necrosis factor, detected directly ex vivo. However, MAIT cells did not offer any protection measured by bacterial clearance.

Secondly, murine Legionella infection also induced MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells, but in contrast, this response was associated with immune protection evident in normal, immunocompetent mice. Peeling away layers of adaptive immunity was revealing. MAIT cell protection was even more apparent in mice lacking CD4+ cells, whilst profoundly immunodeficient RAG2-/-gC-/- mice could be substantially rescued from uniformly lethal Legionella infection by adoptively-transferred MAIT cells. This protection was dependent on MR1, IFN-g and GM-CSF, but not IL-17, TNF-a or perforin.

Protection in the Legionella model was enhanced in mice that were first primed intransally with 5-OP-RU and a costimulus to boost MAIT cells before infectious challenge.  Accordingly, MAIT cells not only protect against the major human lung pathogen Legionella, but can potentially be harnessed as vaccine targets to enhance protection through simple intranasal delivery of purified antigen and a defined adjuvant.