Group A streptococcus (GAS) is a human-restricted pathogen that remains a major worldwide health burden due to the lack of an effective vaccine. Vaccine development has been impeded by various factors including incomplete knowledge of host immunity and correlates of protection against naturally occurring GAS infections.
A recently established controlled human infection model of GAS mediated pharyngitis provided unprecedented insight into the immune response against GAS suggesting an involvement of unconventional T cells (UTC) in the acute inflammatory response.
To define the role of unconventional T cells in anti-GAS immunity, we comprehensively analysed innate and adaptive immune responses of healthy adult PBMC and cord blood cells challenged with irradiated GAS. Using spectral flow cytometry and multiplex cytokine analysis, we identified a discrete cytokine signature after GAS stimulation that was driven by MAIT cell and Vδ2 gamma delta T cell activation, identifying them as major contributors to the early immune response against GAS. This prompt engagement of unconventional T cells was driven by the rapid release of proinflammatory cytokines by monocytes and dendritic cells upon GAS challenge and potently influenced the downstream adaptive T cell response. Furthermore, our work identifies that variations in the quality of the dendritic cell response are a significant factor contributing to differences in unconventional T cell function between GAS naïve and experienced individuals which contributes to our understanding of host protection against GAS throughout life.
These results underline a pivotal role of unconventional T cells in the context of GAS infection and advocates the use of these cells as targets in future human vaccine studies.