Bacterial regulation of early activation of mucosal-associated invariant T (MAIT) cells
Mucosal-associated invariant T (MAIT) cells are a population of CD8+ innate-like T cells that play an important role in the immune response to bacterial infections. Being characterised by the expression of a unique semi-invariant T cell receptor (TCR), MAIT cell TCR-dependent activation is reliant on TCR interaction with MR1 on antigen-presenting cells (APCs). MR1 presents 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a bacterial-derived ligand that is formed by non-enzymatic condensation of 5-amino-6-D- ribitylaminouracil (5-A-RU), produced during bacterial riboflavin synthesis, and methylglyoxal (MG), a by-product of cellular metabolism. Activation generates a pro-inflammatory response, with MAIT cells secreting cytokines such as interferon-γ (IFNγ) and cytotoxic molecules. Previous work has highlighted a difference in activation of MAIT cells by intact and sonicated bacteria, suggesting APCs possess the ability to regulate and direct activation of MAIT cells towards bacteria that are likely to pose an infectious threat. Therefore, in this study, the contribution of bacterial signals to APC regulation of MAIT cell activation was investigated through in vitro peripheral blood mononuclear cell (PBMC) assays, with non-ligand producing E. coli and exogenously added ligand. While bacterial signals were found to enhance early MAIT cell activation, this was related in part to toll-like receptor (TLR) signalling and was not affected by bacterial viability. Modulation of glycolysis in the APC was found to regulate early activation of MAIT cells, with the implication that MG production was enhanced, leading to more efficient conversion of 5-A-RU to 5-OP-RU. However, the dependence of this novel regulatory mechanism for MAIT cell activation on phagocytosis of intact bacteria and activation of endosomal TLRs is still yet to be confirmed. Hence it was concluded that regulation of early MAIT cell activation by APCs is dependent on detection of bacterial signals which may modulate cellular processes, such as glycolysis. In future, this regulatory mechanism could offer a target to modulate MAIT cell activation for the prevention or treatment of bacterial infections.
Advisor: Ussher, James
Degree Name: Bachelor of Biomedical Sciences with Honours
Degree Discipline: Microbiology and Immunology
Publisher: University of Otago
Keywords: MAIT cells
Research Type: Thesis