UBC Theses and Dissertations

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UBC Theses and Dissertations

Immunomodulation of intestinal epithelial cell proliferation and function as a novel host defense mechanism in infectious colitis Chan, Justin


Although epithelial cells represent the primary site of host contact for attaching and effacing pathogens, their contribution to host defense is relatively unrecognized. Both idiopathic and infectious forms of colitis disrupt normal intestinal epithelial cell (IEC) proliferation, differentiation and function, although the mechanisms involved remain unclear. Infection by the attaching and effacing murine pathogen, Citrobacter rodentium leads to significant colonic hyperplasia but also a reduction in colonic goblet cell numbers (goblet cell depletion). This pathology depends on T and/or B cells as Rag1 -/- mice do not suffer this depletion during infection, instead suffering high mortality rates. Reconstitution studies reveal that both CD4+ and CD8+ T cell subsets greatly increase survival of Rag1 -/- mice. However, while mice receiving CD8+ T cells develop exaggerated colonic tissue damage and ulcers, mice receiving CD4+ T cells develop goblet cell depletion in concert with exaggerated IEC proliferation preventing deep pathogen penetration of colonic crypts. Studies with Ifn-γ receptor -/- mice and wildtype mice given IL-17A neutralizing antibodies identify IFN-γ signaling as a critical cytokine required for both goblet cell depletion and increased IEC proliferation. Finally, studies inhibiting notch signaling and thus vastly increasing goblet cell numbers greatly increased pathogen burdens and mortality rates. These studies thus demonstrate that goblet cell depletion reflects host immunomodulation of IEC homeostasis and reflects a novel host defense mechanism against mucosal adherent pathogens.

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