Mucosal associated invariant T cell-mediated vaccination and protection against pathogenic bacteria
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr. Huimeng Wang
Mucosal Associated Invariant T (MAIT) cells are a subset of innate-like T cells, which are abundant in humans. They recognize antigens that are derived from bacterial riboflavin synthesis pathway metabolites, presented by highly conserved MHC-related 1 (MR1) molecules. Upon stimulation, MAIT cells rapidly produce several pro-inflammatory cytokines, such as IFN-γ, IL-17 and TNF-α, and also display direct cytotoxic capacity. These characteristics suggest that MAIT cells play a role in host defence against bacterial infections. Although the microbial reactivity of MAIT cells has been defined, the detailed mechanism by which MAIT cells are activated during bacterial infection in vivo are still not fully understood. Using MR1-tetramers to specifically characterize MAIT cell responses during Salmonella enterica var Typhimurium (S. Typhimurium) pulmonary infection, it is shown in this dissertation that the infection-induced activation of MAIT cells largely depends on the presence of microbial-derived antigens, whereas the expansion of MAIT cells in vivo requires antigens as well as co-stimulatory signals, which can be provided by bacteria or a Toll-like receptor (TLR) agonist. The results presented in this dissertation also demonstrate the protective role of MAIT cells in a murine pulmonary model with a human major pathogen, Legionella longbeachae. In response to infection, MAIT cells proliferate and accumulate at the infection site and contribute to cytokine responses. In the absence of MAIT cells, MR1-/- mice display an impaired and delayed bacterial clearance. MAIT cell-mediated protection is more apparent when CD4+ T cells are removed and can be enhanced by prior expansion with synthetic antigens and an adjuvant (TLR agonists). Notably, adoptively transferred MAIT cells can provide highly immunodeficient Rag2-/-γC-/- mice with full protection against lethal L. longbeachae infection and this protection is achieved, at least in part, by IFN-γ production. In summary, this dissertation provides direct experimental evidence that MAIT cells are protective during bacterial infection. In addition, through exploring the requirements for MAIT cell activation and expansion in vivo, the studies revealed that the pre-expanded MAIT cells in mice were potentially protective and to suggest that MAIT cells can be harnessed as a vaccine target to elicit a “memory”-type protection.
Keywordscellular immunology; infectious disease
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