Date of Award

2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

David Artis

Abstract

This thesis characterizes and explores the role of thymic stromal lymphopoietin (TSLP) – TSLP receptor (TSLPR) interactions in the regulation of intestinal immunity and inflammation. TSLP is known to promote TH2 cytokine-mediated inflammation in the skin and the lung. Firstly, this thesis focuses on the characterization of TSLP and TSLPR expression within the gastrointestinal (GI) tract and in the immune cells of the associated lymphoid tissues. Our findings suggest that TSLP is primarily produced by intestinal epithelial cells (IECs) under homeostatic conditions. Expression of the heterodimeric TSLPR complex was exhibited on gut-associated lymphoid tissue (GALT) CD4+ T cells and CD11c+ dendritic cells (DCs) as well as on splenic mast cells and basophils in naïve mice. Second, this thesis explores the role of TSLP in the generation of a TH2 cytokine-mediated host-protective immune response to the gastrointestinal helminth pathogen Trichuris muris. We demonstrate that in an intact animal TSLP-TSLPR interactions are critical for resistance to Trichuris as disruption of the TSLP-TSLPR pathway either through genetic deletion of the TSLPR, or antibody-mediated depletion of TSLP, resulted in susceptibility to infection. Further, these mice exhibited increased infection-induced proinflammatory cytokine production and inflammation. However, TSLP-TSLPR interactions were not required for the generation of a host-protective TH2 cytokine-mediated immune response to Trichuris in the absence of IFN-γ, indicating TSLP-independent intestinal TH2 immune responses. Third, we examine the potential for TSLP-TSLPR interactions to regulate intestinal proinflammatory cytokine production. Examination of naïve TSLPR-/- mice revealed a trend towards increased CD4+ T cell production of IFN-γ in the GALT compared to TSLPR+/+ mice. Further, TSLPR-/- mice were more susceptible to DSS-induced colitis, exhibiting increased proinflammatory cytokine production and more severe intestinal inflammation compared to control mice. We demonstrate that TSLP can regulate DC-derived IL-12/23p40 production both in vitro and in vivo and that rTSLP is able to inhibit CD4+ T cell production of IFN-γ in splenocyte cultures in the absence of IL-4. Taken as a whole, this thesis identifies an important role for TSLP-TSLPR interactions in regulating intestinal immunity and inflammation and in the maintenance of intestinal immune homeostasis.

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