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Microbial regulation of tolerogenic dendritic cells in oral tolerance

Award Number: R21AI199495
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/04/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Microbial regulation of tolerogenic dendritic cells in oral tolerance - Project Summary Celiac disease (CeD) is a chronic immune-mediated disorder triggered by gluten ingestion in genetically susceptible individuals and currently lacks a curative treatment. The only available therapy is a lifelong gluten- free diet (GFD), which is burdensome and frequently ineffective, leaving 40-60% of patients symptomatic, underscoring the urgent need for alternative therapeutic strategies. CeD is marked by a loss of oral tolerance (LOT) to gluten, which precedes disease pathology. In genetically susceptible hosts, LOT is driven by proinflammatory dendritic cells (DCs) that promote proinflammatory T helper 1 (Th1) responses to dietary gluten, rather than tolerogenic regulatory T cell (Treg) responses. While HLA-DQ2 or DQ8 alleles are necessary for disease development, they are not sufficient, pointing to the role of environmental factors such as viruses and commensal gut microbes in shaping oral tolerance. We have gained significant insights into the mechanisms of how microbes’ impact oral tolerance. Our prior work showed that enteric infection with reovirus promote LOT to gluten, while colonization with a gut commensal protist protects against this effect. We also make use of MHC-II-restricted gluten tetramers that allow us to track gluten-specific T cell responses under physiologically relevant conditions. Recently, several independent laboratories provided strong evidence that DCs expressing the transcription factor RORgt (RORgt+ DCs) are essential for promoting oral tolerance by promoting Treg responses to dietary model antigen ovalbumin. This suggests that the effects of viruses and protists on oral tolerance may, at least in part, be modulated through RORgt+ DCs. Using genetic models to selectively and inducible deplete RORgt+ antigen-presenting cells and cutting edge tools to track gluten-specific T cell responses, we will: (1) test the requirement for RORgt+ DCs in regulating virus- induced LOT, restoring oral tolerance, and mediating protist dependent protection against virus-induced LOT and (2) determine how virus infection and protist colonization transcriptionally and functionally modulate RORgt+ DCs. Understanding how microbes modulate tolerogenic DCs will illuminate novel mechanisms of CeD pathogenesis and identify therapeutic targets for restoring oral tolerance to gluten in patients with CeD.


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 = $237,919 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	5/5/2026	NEW	$237,919
														Subtotal = $237,919

Grand Total All Awards = $237,919

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Microbial regulation of tolerogenic dendritic cells in oral tolerance

Award Number: R21AI199495

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/04/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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