MR1 surface expression on primary blood cells and their role in mucosal associated invariant T (MAIT) cell activation
Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes that bridge the innate and adaptive immune systems to provide rapid effector responses against a broad range of bacteria. MAIT cells are characterised by a semi-invariant Va7.2- Ja33/12/20 T cell receptor (TCR), which is restricted by the MHC-I-like molecule, MHC-related protein 1 (MR1). MR1, expressed on antigen presenting cells (APCs), binds and stabilises the MAIT cell activating ligand, an unstable pyrimidine, formed by the condensation of 5-amino-6-D-ribitylaminouracil (5-A-RU), an intermediate in riboflavin biosynthesis, with methylglyoxal (MG). Recognition of this MR1-presented ligand by MAIT cells results in TCR-mediated activation, which in turn results in the secretion of pro-inflammatory cytokines and cytotoxicity. Recent data generated using THP1 cells, a human monocytic cell line, as APCs, suggests that additional bacterially- derived signals also regulate MAIT cell activation. It is unknown whether these signals are also important in primary APCs. In this study, in vitro assays were performed to determine the regulation of MR1 surface expression on primary blood cells and the ability of primary blood cells to activate MAIT cells; a non-riboflavin-synthesising bacterial strain and synthetic MAIT cell activating ligand, 5-A-RU/MG, were used to separate the effects of different signals. The majority of primary blood cells showed enhanced MR1 surface expression in response to 5-A-RU/MG, but this was not enhanced by bacteria, except for CD14loCD16+ monocytes. While bacterial enhancement of MAIT cell activation in response to 5-A-RU/MG was also seen with primary APCs, it was dependent upon the presence of a CD8+ population in co-culture; the importance of this CD8+ population was also evident with THP1.hMR1 cells. In summary, this study has identified MR1 expression by a range of primary cells and a role for a CD8+ cell population in enhancing TCR-mediated MAIT cell activation by primary APCs in the presence of bacteria.
Advisor: Ussher, James
Degree Name: Bachelor of Biomedical Sciences with Honours
Degree Discipline: Microbiology and Immunology
Publisher: University of Otago
Keywords: MAIT; cells; innate-like; lymphocytes; immunology; bacterial response; MR1; Mucosal; 5-A-RU; blood; B cells; T cells; monocytes; antigen presenting cells
Research Type: Thesis