Perinatal infection elicits clonally restricted T follicular helper cell responses that drive antibody-mediated viral control.

Perinatal infection often results in viral persistence, as observed for hepatitis B virus in humans. Commonly held concepts suggest that persistence is associated with immunotolerance, but this fails to predict the emergence of antiviral antibodies and eventual viral load control. Studying perinatal lymphocytic choriomeningitis virus (LCMV) infection, the prototypic mouse model of neonatal antiviral immunotolerance, we observe antibody-mediated viral load suppression and canonical germinal center (GC) reactions. This neonatal response is driven by antiviral CD4+ T follicular helper (Tfh) cell responses. However, viral epitope-specific CD4+ T cells in perinatally infected animals are less abundant and less clonally diverse than in adult-infected mice. Furthermore, CD4+ T cell supplementation augments GC responses in perinatally, but not adult, infected mice. Hence, humoral immune defense is partially exempt from neonatal tolerance. More broadly, the numerically and clonally restricted CD4+ Tfh response lends itself as an immunotherapeutic target for a functional cure.