PROJECT SUMMARY To maintain health, the host must avoid generating inflammatory responses to beneficial gut bacteria, while retaining the ability to respond to pathogens. Maintaining this balance is particularly complicated in early life as many of the mechanisms that serve to promote tolerance to resident commensal microbes in adults are either absent or not yet established during this period. We recently identified maternal antibodies as key regulators of host-microbiota mutualism in neonates. Specifically, we found that in addition to IgA, healthy mothers generate microbiota-reactive IgG antibodies, which are transmitted via breastmilk and coat bacteria in the neonatal gut. In comparison with control offspring, neonates that do not receive these maternal isotypes harbor increased numbers of commensal bacteria in gut draining lymph nodes, mount inappropriate, microbiota-driven CD4 T- dependent immune responses, and suffer increased morbidity when subjected to a chemical form of colitis. Building from these exciting findings, this proposal seeks to understand the mechanisms by which maternal antibodies regulate nascent host-microbiota interactions in neonates. Specifically, we will determine the antigen specificities and the effector mechanisms (e.g., complement activation or Fc receptor ligation) required for distinct maternal IgG isotypes to restrain neonatal adaptive immune responses to beneficial gut bacteria. Additionally, we will define the signaling pathways and cell types required to trigger dysregulated adaptive immune responses in offspring that do not receive breastmilk antibodies. We will employ innovative approaches to achieve these goals by leveraging fostering and optimized infant feeding approaches with transgenic mouse models and multi-parameter flow cytometry. These studies are significant because they address key gaps in our knowledge regarding how favorable relationships between the host and resident microbiota are established in early life. Additionally, our work will also advance our understanding of the mechanisms by which breastfeeding promotes health. We expect that the insight gained from this research will significantly aid in our ability to manipulate host-microbiota interactions and mucosal immunity during early life, regardless of mode of nutrition.