CD40-CD154 Interactions in Cryptosporidial Immunity

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DESCRIPTION (Provided by the applicant): Cryptosporidium parvum (CP) causes prolonged and severe infections in humans with AIDS or mutated CD154 genes (X linked immunodeficiency with hyper IgM, or XHIM) leading to sclerosing cholangitis and liver failure. CP infects gut epithelial cells that normally end their lifespan engulfed by dendritic cells (DC) in the lamina propria. The hypothesis underlying this application is that 'a CD40 signal is necessary for CP to be killed by DC'. This hypothesis predicts that intact, viable, CP will reach the mesenteric lymph node (MLN) when there is no CD40-CD154 signal. The underlying hypothesis accounts for the requirement for CD4 T cells that express CD 154, and marrow-derived CD40+ cells, for mice to recover from a CP infection. It raises the question: do the CD154+ CD4+ T cells required to clear CP have to be CP-specific? We found that RAG-/- mice expressing transgenic T cell receptors (Tg) for ovalbumin (or cytochrome c) recover from CP infections. Our preliminary data will show that adoptively transferred DO11.10 T cells are activated in the MLN of CP-infected RAG-/- mice provided that they are in an MHC matched environment. Our Specific aim one will determine whether E aboutxAI3 transgenic mice can clear a CP infection. This approach tests the hypothesis that the loading of antigen peptides onto self-MHC is required for a CP infection to be cleared from the gut. Secondary approaches under Aim 1 will (a) test the hypothesis that transgenic CD4 cells clear CP infections only in the MHC environment in which they were selected. In lc the requirements for IL-12, B7 and CD28 for activation of Tg and wild type CD4 cells will be compared. Specific Aim two will test the hypothesis that lamina propria DCs require a CD40 signal to degrade the proteins and nucleic acids of endocytosed CP and epithelial cells. These aims are selected because they address issues critical for under- standing immunity to CP and the immunopathology that results when an infection is not eradicated. Mechanisms established in CP infections are likely to be relevant to other important intracellular pathogens, particularly Microsporidia and Toxoplasmah sp. The results will be important for immunodeficient humans chronically infected with the parasite.