γδ T Cells Contribute to Immunopathology During Neonatal Sepsis in an Age-Dependent Manner

Abstract

Abstract Bacterial bloodstream infections (BSIs) remain a significant contributor to neonatal mortality, despite improved hygienic practices in the NICU. Although the understanding of the neonatal immune system has increased greatly over the past decade, why neonates, but not older infants, are susceptible to severe adverse immunopathology – sepsis – in response to bacteremia remains poorly understood. In the present study, we find that postnatal day 5 (P5) neonatal γδ T cells are highly inflammatory during a mouse model of E. coliBSI and are associated with mortality. Furthermore, γδ T cells in P5 mice rapidly produce pro-inflammatory cytokines, such as IFN-γ, IL-17A, and TNFα, and increase their expression of cytotoxic molecules such as granzyme and perforin. Interestingly, blockade of the γδ TCR in vivois associated with increased survival and decreased pro-inflammatory cytokine production in P5 pups. Signaling and activation via the γδ TCR was confirmed using Nur77-GFP mice, with P5 γδ T cells significantly upregulating expression of Nur77 during in vivoinfection. Intriguingly, E. coliBSI in P15 pups results in markedly different γδ T cells responses compared to neonates, despite similar systemic bacterial burden. During bacterial bloodstream infection, P15 pups do not experience mortality, and unergo minimal activation of γδ T cells and production of IFN-γ, IL-17A, and TNFα. Furthermore, BSI infection in P15 Nur77-GFP mice revealed lack of TCR signaling in P15 γδ T cells at this age. In conclusion, the present study reveals rapid age-dependent changes to γδ T cell responses during early life and suggests neonates may be uniquely susceptible to γδ T cell-mediated immunopathology during bacterial bloodstream infection. T32 AI170478-01