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Influence of Maternal IgA on Neonatal iNKT Cell Development and Gluten Sensitive Enteropathy.

Award Number: F31AI191759
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/15/2025
PERIOD OF PERFORMANCE END DATE: 05/14/2028

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $42,354 )
2026	2026	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	000	2	5/7/2026	NON-COMPETING CONTINUATION	$42,354
														Subtotal = $42,354

Issue Date FY: 2025 ( Subtotal = $41,778 )
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	004	1	8/4/2025	NEW	$564
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	001	1	3/31/2025	NEW	$0
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	003	1	5/28/2025	NEW	$0
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	002	1	3/31/2025	NEW	$0
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	000	1	3/31/2025	NEW	$41,214
														Subtotal = $41,778

Grand Total All Awards = $84,132

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Influence of Maternal IgA on Neonatal iNKT Cell Development and Gluten Sensitive Enteropathy.

Award Number: F31AI191759

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/15/2025

PERIOD OF PERFORMANCE END DATE: 05/14/2028

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