Effects of breast milk antibodies on neonatal intestinal immunity and host-microbe mutualism

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Project Summary/Abstract Breast milk is a key regulator of host-microbiome interactions in early life. In addition to nutrients, breast milk contains cytokines, growth factors and antibodies, which help shape the composition of the microbiota and regulate infant immunity to gut microbes. Accumulating evidence links breastfeeding with a decreased risk of developing immune-mediated and metabolic diseases later in life. However, the specific components of breast milk and the mechanism underlying these associations are currently lacking. Using a mouse model, our lab discovered that mice deficient in breast milk antibodies mount increased mucosal T cell- dependent immune responses, including elevated T follicular helper (Tfh) cells and germinal center (GC) B cells in the gut-draining lymphoid tissues. This process is driven by microbes as germ-free mice lacking breast milk antibodies do not generate aberrant mucosal Tfh and GC B cell responses. Due to the profound impact of the gut microbiota on the development of the immune system coupled with the lifelong persistence of activated adaptive immune cells, a current paradigm is that inappropriate adaptive immune responses to gut bacteria drive adverse health outcomes in the long-term. The hypothesis of this proposal is that inappropriate adaptive immune responses to resident gut bacteria resulting from the absence of breast milk antibodies drives persistent impairments in intestinal homeostasis. To test this hypothesis, two aims are proposed. Aim 1 investigates the persistence, localization, and phenotype of B cells activated in the absence of maternal antibodies via fate-tracking activated GC B cells and flow cytometry. Aim 2 assesses the function of the T cell dependent adaptive immune response on intestinal homeostasis. The comprehensive phenotypic and functional characterization of the novel T cell dependent immune response that arises in neonates lacking breast milk antibodies will provide key mechanistic insight on how breastfeeding contributes to long-term health. The studies outlined here will lay the groundwork for the development of interventions and therapies to manipulate host relationships with the microbiota and promote long-term health, particularly in neonates who are not breastfed.