Staphylococcus aureus is a major human pathogen of multiple tissue sites. The emergence of antibiotic-resistant strains promises greater morbidity in the future. No S. aureus vaccine has so far succeeded in translating murine immunity to human patients. Unconventional T cells may be crucial for responses to S. aureus. Murine γδ T cells mediate immunity to S. aureus, and MAIT cells respond to S. aureus antigens in vitro. However, the mechanics of these responses remain unclear. Here I have investigated the potential for S. aureus-induced activation of human γδ T and MAIT cells to aid in the development of the S. aureus vaccine. I have found that while γδ T cells respond rapidly and robustly in the mouse, these responses were tissue-specific. I have also found a number of clear disparities between γδ T cell responses of mice and humans, helping to explain repeated failed vaccines. In co-culture with infected DCs, I have found that Vδ2+ cells secrete high levels of IFNγ, a response initiated by DC contact and enhanced by IL-12. In return, γδ T cells upregulate DC activation in a positive feedback loop. I have also found that activation of CD4+ T cells in co- culture is also enhanced by γδ T cells. I have also investigated the potential for S. aureus to activate MAIT cells, and found that after binding of DC-expressed MR1, MAIT cells commenced secretion of both IFNγ and cytotoxic mediators. My findings implicate these unconventional T cell subsets in important, rapid anti-S. aureus responses that may be of great relevance to the ongoing development of novel anti-S. aureus treatments.

APPROVED