Sunday, May 18, 2025
5/18/2025
Influence of Maternal IgA on Neonatal iNKT Cell Development and Gluten Sensitive Enteropathy. - PROJECT SUMMARY______________________________________________________________________ Early maternal-offspring interactions, such as the transfer of IgA through breast milk, are key in shaping mucosal immunity and microbiota composition. Correlative studies suggest that individuals who were formula-fed are at a higher risk of gluten sensitivities, underscoring the importance of maternal influence in early life. Maternal factors may play a role the in the prevention of gluten sensitivity by promoting the development of immune tolerance towards dietary antigens during the neonatal period. Recently, our lab has described two mouse models of spontaneous gluten sensitive SI enteropathy (JH-/- and CD19-/-). Here, we provide pilot data demonstrating that IgA-/- mice are uniquely susceptible to gluten sensitive enteropathy that is associated with defects in tolerogenic iNKT cell phenotypes. We also demonstrate that gluten sensitivity in our model is a transmissible (i.e. microbiota-dependent) phenotype, and that a lack of early life exposure to maternal IgA results in chronic defects in tolerogenic iNKT cells. Our overarching hypothesis is that maternal IgA is essential for the development of tolerogenic iNKT cells in the neonatal period, which suppresses gluten sensitivity later in life. The objective of Specific Aim #1 is to test whether maternal IgA prevents the development of gluten sensitivity in adult offspring. To do this, we will utilize breeding strategies of IgA-sufficient (IgA+/-) and IgA-deficient (IgA-/-) dams and then cross-foster mixed litter offspring (IgA+/-, IgA-/-) between dams. Fostered offspring will then be placed on a gluten free diet (GFD) or nutritionally matched gluten rich diet (GRD). After four weeks (when animals are 8 weeks old), SI resident immune cells and luminal contents will be assessed through high- parameter flow cytometry, 16S rRNA sequencing, histological analysis, and ATAC-scRNA sequencing on T cells and iNKT cells. The objective of Specific Aim #2 is to test whether there is a critical postnatal window during which maternal IgA reinforces a tolerogenic iNKT cell developmental program. To do this, we will colonize germfree (GF) WT and GF IgA-/- pregnant dams with WT SIM or a species of Streptococcus isolated from our colony. A timed cross-fostering approach will then be applied to determine the critical time window for tolerogenic iNKT cell development. Bacterial meta-transcriptomics, flow cytometry, and RNA sequencing will then be performed on adult offspring to explore the time-dependent impact of maternal IgA on neonatal microbial colonization and function as well as the effects on mucosal immunity and iNKT cell development. Through these aims, we will address a major gap in our knowledge regarding the effect of the maternal environment on the development of gluten sensitivity later in life. Additionally, results from our experiments will identify novel mechanisms by which maternal IgA influences immunological tolerance that could lead to novel therapeutic strategies to prevent or treat gluten-sensitivity.
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