Immune Modulation of Intestinal Goblet Cell Responses

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DESCRIPTION (provided by applicant): Intestinal nematode infections are a major cause of morbidity and mortality throughout the world, affecting up to one quarter of the world's population. I describe a unique goblet cell-specific protein called RELMB which is secreted apically into the intestinal lumen, where it plays a novel role in vertebrate resistance to intestinal parasitic infection. It has been established that Th2-mediated intestinal inflammatory responses, typified by host responses to nematode infection, lead to goblet cell hyperplasia. Very little is currently known about the mechanisms by which the host immune system regulates the development of the goblet cell-specific genes in response to nematode infection. Using RELMB as a model, I show that goblet cell development in the intestinal tract is regulated by the intestine-specific transcription factor, Cdx2. I further demonstrate that RELMB expression can be induced by bacterial colonization in the absence of the acquired immune system, and that highest levels of RELMa expression are induced by intestinal nematode infection. My overall hypothesis is that basal intestine-specific activation of [sic] the RELMB promoter requires the Cdx family of transcription factors, and that TLRs and their downstream signaling pathways synergize with Th2-mediated pathways to optimally activate goblet cell responses to parasitic infections. 3 Specific Aims will be pursued: 1) The functional importance of NFkB and Stat6 cis-acting elements within the RELM-B promoter will be studied in vitro, and synergism with Cdx2 will be investigated. 2) A Trichuris muris model of murine nematode infection will be studied in mice with targeted deletions of MyD88, NFkB1, and Stat6 to determine the effect on RELMa expression. 3) Adoptive T cell transfer studies will be performed in T. muris infected SCID mice to determine the role of CD4+ T cells and Th2 cytokines in RELMB expression and nematode expulsion. My results will provide insight into the interactions between host innate and adaptive immunity, and will elucidate mechanisms by which goblet cells function as immune effector cells in the colon.