Date of Award
6-23-2025
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The intestinal immune system plays a critical role in maintaining a delicate balance between immune tolerance to dietary and commensal antigens and effective defense against pathogens. This dissertation presents two independent but conceptually linked studies that investigate distinct immunological mechanisms contributing to intestinal homeostasis. The first study examines the role of the complement system, specifically complement component C3, in mucosal defense against Vibrio cholerae infection. To more accurately investigate in vivo host responses to cholera toxin, we developed the first adult (juvenile) mouse model of cholera toxin–mediated pathogenesis during V. cholerae infection. Using this model, we found that cholera toxin induces robust C3 expression in the gut, originating from multiple cell types, including epithelial cells, stromal cells, and immune cells. We further demonstrate that epithelial-derived complement activation plays a pivotal role in preserving intestinal barrier integrity during infection, without significantly affecting bacterial burden. The second study investigates how the intestinal regulatory T cell (Treg) repertoire is shaped by exposure to self, dietary, and microbial antigens. Using gnotobiotic and germ-free TCRβ-transgenic mice, combined with high-throughput TCRα sequencing, we classified Treg TCRs based on antigen origin and analyzed how colonization with defined bacterial consortia, including human-derived Clostridiales isolates and mouse Helicobacter species, differentially influences the colonic Treg landscape. In vitro validation confirmed that repertoire-based antigen predictions accurately reflect TCR specificity, revealing that distinct microbial species can imprint unique antigenic signatures on the intestinal Treg compartment. Together, these studies highlight complementary innate and adaptive mechanisms by which the immune system preserves gut integrity and immune tolerance. By dissecting the contributions of complement and regulatory T cells to intestinal immunity, this work advances our understanding of the dynamic interplay between the host and its microbial environment, with implications for infection, autoimmunity, and microbiota-targeted therapies.
Language
English (en)
Chair and Committee
Meng Wu
Committee Members
Andrew Kau; Christina Stallings; Chyi Hsieh; Megan Baldridge
Recommended Citation
Peng, Yangqing, "Balancing Defense and Tolerance: Complement-Mediated Pathogen Protection and Commensal Microbial Antigen-Specific Regulatory T Cell Responses in the Gut" (2025). Arts & Sciences Theses and Dissertations. 3458.
https://openscholarship.wustl.edu/art_sci_etds/3458