Breastmilk antibody isotypes differentially protect against neonatal rotavirus infection and modulate the timing and clonal architecture of offspring B cell responses

Abstract

Mother-to-offspring transfer of antibodies protects newborns during the critical phase of early life, preventing both infection and inflammation. Whether and how pre-existing passive immunity actively shapes immune memory formation in neonates remains unclear. Using a murine neonatal Rotavirus infection model in combination with cross-foster approaches and genetic models, we disentangled the contribution of maternal IgA and IgG to neonatal immune outcomes. While breastmilk antigen specific IgA is responsible for protection from Rotavirus infection, antigen specific IgG delays pup-intrinsic humoral immune induction to after weaning. Importantly, pre-existing maternal immunity delays and constrains, rather than ablates, long term humoral immunity. Together, our data move beyond a binary view of passive immunity as protective versus inhibitory, providing a more nuanced understanding in which breastmilk antibodies actively program the neonatal response for optimal immediate protection and long-term immune education in the growing organism.