Streptococcus pyogenes or group A streptococcus (GAS) is a human-restricted pathogen that remains a leading cause of infection related mortality due to the lack of an effective vaccine. Vaccine development has been impeded by various factors including incomplete knowledge of host immunity against naturally occurring GAS infections.
Utilising a recently established human infection model of GAS mediated pharyngitis, we provided unprecedented insight into the immune response to GAS describing an in vivo immune signature during the initial phase of infection. This immune signature identified the involvement of unconventional T cells in the acute inflammatory response. To further elaborate the role of unconventional T cells in anti-GAS immunity, we established an in vitro co-culture system to simultaneously interrogate various innate and adaptive immune cell subsets from adult peripheral blood and umbilical cord blood mononuclear cells challenged with irradiated GAS. Using spectral flow cytometry and multiplex cytokine analysis, we observed a broad, pro-inflammatory cytokine signature and identified unconventional T cells, specifically MAIT and Vδ2+ gamma delta T cells, as the main drivers of the early T cell response after GAS stimulation. This prompt engagement of unconventional T cells directly depended on a rapid release of cytokines by monocytes and dendritic cells upon GAS challenge. Furthermore, our work identifies variations in the quality of the unconventional T cell response 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.