Human unconventional T cells shape the early immune response to Group A Streptococcus 3467

Abstract Description Streptococcus pyogenes or Group A streptococcus (GAS) is a human-restricted pathogen that continues to represent a major worldwide health burden. The development of protective vaccines has been impeded by several factors including incomplete knowledge of host immunity against naturally occurring GAS infections. Utilizing a human infection model of GAS mediated pharyngitis, we provided unprecedented insight into the in vivo immune response to GAS revealing an involvement of unconventional T cells (UTC) in the acute inflammatory response. By employing high dimensional flow cytometry and cytokine analysis of adult PBMC and cord blood cells challenged with various clinically relevant strains of GAS, we observed a broad, pro-inflammatory cytokine signature and identified Vδ2+ gamma delta T cells and MAIT cells as the main drivers of the early T cell response following GAS stimulation. This prompt engagement of unconventional T cells was directly dependent on a rapid release of IL-12, IL-18 and TNFα by monocytes and dendritic cells and was severely impaired in GAS-naïve cord blood. These findings contribute to our understanding of host protection against GAS throughout life which was further strengthened by our analysis of GAS-colonized tonsil tissue to elucidate the in situ immune response to GAS. Overall, these results underline a pivotal role of unconventional T cells in the context of GAS infection and advocate for the use of these cells as targets in future human vaccine studies. Topic Categories Immune Mechanisms of Human Disease (HUM)