Group A streptococcus (GAS) is a human-restricted pathogen that is responsible for over 600 million infections and 500,000 deaths each year, remaining 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.
To decipher the immune response to GAS infection, we are utilizing controlled human infection models, primary tonsil organoids, and in-vitro infection assays of peripheral blood mononuclear cells (PBMC) and cord blood mononuclear cells (CBMC) stimulated with various clinically relevant strains of GAS. Through high-dimensional flow cytometry and multiplex cytokine analysis, we identified a proinflammatory cytokine signature following GAS stimulation that was driven by activation of the unconventional T cell subsets, MAIT and Vδ2+ γδ T cells.
This activation directly depended on monocyte and myeloid dendritic cell derived IL-12, IL-18, and TNFα, which was released prior to T cell activation. Notably, activated MAIT and Vδ2+ γδ T cells were the main drivers of the early proinflammatory T cell response, accounting for more than half of all IFNγ producing cells. We also detected this unconventional T cell signature in primary human tonsil samples suggesting that these cells represent a first line of defense against GAS infection. Intriguingly, the response of unconventional T cells from cord blood was significantly blunted compared to adult PBMC potentially explaining the increased susceptibility of infants and young children to GAS infection.
Overall, these results underline a pivotal role of human MAIT and Vδ2+ γδ T cells in the context of GAS infection and advocate for the use of these cells as targets in future human vaccine studies.