Age-Dependent Responses of γδ+ T cells During Bloodstream Infection in Early Life

Abstract

Late-onset neonatal sepsis (LOS) is a bloodstream bacterial infection that occurs during the first two months of life. Despite improved clinical care, LOS remains a significant contributor to neonatal mortality. Clinical observations suggest neonates exhibit unique immune responses and excessive inflammation during sepsis compared to adults and older children, however, factors contributing to these differences remain poorly understood. Two common routes of pathogen entry for neonates are direct introduction of a pathogen into the bloodstream, or the translocation of a gut-resident pathobiont. Our lab has developed a mouse model of LOS that disrupts goblet cell homeostasis to increase gut permeability and facilitate the translocation of virulent bacterial species such as E. coli. During both intraperitoneal and oral infection, we observe several key features of clinical LOS including increased pro-inflammatory serum cytokines, organ failure, and death in 5 day-old pups, but not 15 day-old pups. Strikingly, we have found robust activation of γδ+ T cells in 5 day-old pups, following infection, independent of pathogen entry route. This γδ+ T cell activation occurred in an age-dependent manner and was absent in 15 day-old pups. γδ+ T cell activation in 5 day-old pups was also associated with a pro-inflammatory cytokine profile that was absent in older pups. Finally, 5 day-old TCRδ−/− pups were protected from mortality during LOS, suggesting that γδ+ T cells may also contribute to mortality in this model. This study sheds light on the unique responses of γδ+ T cells to bloodstream infection during two distinct periods of early life.