Harnessing the Potential of MAIT Cells as Cellular Adjuvants in Mucosal Vaccines

Abstract

The development of vaccines is considered one of the most successful medical interventions to date, preventing millions of deaths every year. However, the majority of vaccines are administered peritoneally, despite the vast majority of pathogens invade the human host at mucosal sites. By vaccinating at distal sites, little to no protection is developed at the mucosa where the initial invasion occurs. There are however, a handful of licenced mucosally administered vaccines against infections such as poliovirus, influenza and Salmonella Typhi that are able to induce both a systemic and mucosal protective immune response. All but one of the current licenced mucosal vaccines are live attenuated due in part to the difficulty of developing new mucosal adjuvants. Recombinant cholera toxin subunit B is the only adjuvant used in the current licenced mucosal vaccines. While inactivated and subunit vaccines are considered safer as they are unable to revert back to virulent pathogens, adjuvants are required to boost their immunogenicity. This thesis therefore explores whether mucosal-associated invariant T (MAIT) cells which are found in mucosal tissues, are invariant in nature and have rapid activation, could be exploited as cellular adjuvants in mucosal vaccines.

This thesis was able to show that intranasally administered MAIT cell agonist components, 5-A-RU and methylglyoxal (MG), are able to induce both MAIT cell and conventional dendritic cell (cDC) activation in the lung tissue and mediastinal lymph node (mLN). In this model CD40L and RANKL co-stimulatory interactions are involved in ICOSL expression on cDCs in the lung and associated with cDC activation. The MAIT cells within this model also maintained a RORyT and GATA3 phenotype after both one and three doses of the 5-A-RU + MG vaccine. Furthermore, a prime-boost intranasal vaccine scheme of 5-A-RU + MG and the model antigen OVA, was able to induce MR1-dependent accumulation of TFH cells and antigen-specific germinal center B cells in the mLN along with systemic antigen-specific IgG antibody production. This humoral response was also dependent on the presence of both cDC1 and cDC2 populations. Together, this thesis suggests MAIT cells have the potential to be utilised as cellular adjuvants in mucosal vaccines.