Intestinal CD4+T Cell Responses to Food

<p>During routine digestion and absorption of food, massive quantities of diet-derived polypeptides pass through the intestine. The intestinal immune system must maintain tolerance to these dietary antigens while still protecting against pathogens and noxious agents. Oral tolerance, a robust mechanism whereby oral administration of antigen results in both local and systemic tolerance to that antigen, is a key component of this critical homeostasis. Oral tolerance requires CD4⁺ T cells including specifically regulatory T cells (Tregs), however the role of intestinal CD4⁺ T cells and the T cell repertoire in a physiological response to food protein remains largely unexplored. To characterize intestinal T cell responses to food protein, we developed a protein antigen-free solid diet which we either supplemented with a single model food protein (OVA) or compared to complex chow diet containing diverse proteins and metabolites. We found that at steady state, chow diet promotes epithelial adaptation and cytotoxic programming of intestinal CD4⁺ T cells including Tregs, a pathway which is further boosted by signals from the microbiota. We also observed a strong bias towards clonal selection of mature intestinal CD4⁺ T cells by dietary proteins, suggesting that food antigen-specific intestinal CD4⁺ T cells are generated in the course of eating. Finally, we show that intestinal inflammation induced by cholera toxin (CT) led to increased tissue infiltration of CD4⁺ T cells, enriched for Th17 rather than epithelium-adapted cells. Protection against CT-induced food allergy was associated with clonal expansion of Tregs and reduced pro-inflammatory gene expression signature, while development of food allergy was associated with proinflammatory Th17 and immune exhaustion. Altogether, these findings suggest that highly regulated maintenance of cytotoxic epithelium adapted CD4⁺ T cells in addition to Tregs may be critical for preventing inappropriate immune responses to food and subsequent disease.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2022

Author dc:creator

• Lockhart, Ainsley

Contributors dc:contributor

• Daniel Mucida

• oral tolerance
• CD4+ T cells
• Tregs
• food antigens
• intestinal immunity
• Th17
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/688

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1687