Meningeal γδ T cells facilitate bacterial entry into the brain in neonatal meningitis and trigger long-term behavioural sequelae

Abstract

Neonatal bacterial meningitis is a life-threatening condition and a leading cause of neurodevelopmental impairment among survivors. Despite its prevalence, the role of meningeal immunity on disease pathology during early life remains largely unexplored. Using a clinically relevant mouse model of neonatal group B streptococcal meningitis and single-cell RNA sequencing, we observed that IL-17A (IL-17)-producing {gamma}{delta} T cells ({gamma}{delta}17 T cells) accumulate in the meninges during the acute phase of infection and persist throughout the lifespan. Importantly, mice deficient in {gamma}{delta} T cells or in IL-17 show a significantly lower bacterial colonisation in the brain parenchyma, and IL-17 neutralisation in the cerebrospinal fluid leads to a similar phenotype. Reduced blood-brain barrier permeability in the absence of {gamma}{delta} T cells results in decreased bacterial invasion and diminished microglia activation. Wild-type but not {gamma}{delta} T cell-deficient mice surviving infection exhibit increased hyperactivity and open space anxiety during early adulthood, a behavioural profile that may reflect attention deficit and hyperactivity (ADHD)-like tendencies. Altogether, these findings establish a pathogenic role for meningeal {gamma}{delta}17 T cells in early life, uncovering a key mechanism that drives long-term sequelae in GBS neonatal meningitis.