Antiviral Tfh response by “tolerant” congenitally infected virus carriers drives antibody-mediated viral load control [scRNA-Seq]

Congenital infection can result in viral persistence as commonly observed for hepatitis B virus in humans. The accompanying “neonatal tolerance” state remains immunologically ill-defined and treatment options are unsatisfactory. Studying congenital lymphocytic choriomeningitis virus infection, the prototypic mouse model of neonatal antiviral tolerance, we observe antibody-mediated suppression of viral replication. These responses are driven by canonical antiviral CD4 Tfh responses, whereas CD8 T cells are irrelevant for viral load control. Viral epitope-specific CD4 T cells of congenitally infected animals are less abundant than in adult infection. They exhibit reduced clonal diversity and distinct differences in gene expression patterns. Importantly, exogenous supplementation of T help augments antiviral germinal center B responses of congenitally infected mice. These findings reveal that humoral immune defense is partially exempt from neonatal tolerance and remains effective against congenital infection. Imperfect virus control by limited CD4 Tfh responses may offer opportunities for a functional cure by immunotherapy.