CD40-CD154 Interactions in Cryptosporidial Immunity

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DESCRIPTION (provided by 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) with the development of sclerosing cholangitis and a need for liver transplant. 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 'DC require a CD154 signal to kill ingested CP' and that, without the CD154-CD40 signal, intact CP reach the mesenteric lymph node (MLN). This hypothesis accounts for the requirement for CD4 T cells that express CD154, and marrow-derived CD4O+ cells, for mice to recover from a CP infection. Our recent report that RAG-/- mice expressing transgenic T cell receptors for ovalbumin (or cytochrome c) recover from CP infections shows that a non-classical pathway suffices for the T cell activation and the expression of CD154 that is necessary for CP clearance. Preliminary studies will show that CP clearance requires class H expression as well as CD4 T cells - suggesting that affinity for a self peptide plus MHC is required for CP-stimulated T cell activation. This observation is the basis for the hypothesis tested in Aim 1: that affinity for a self-MHC complex is required for T cell activation in response to CP. We predict that lamina propria DCs upregulate their cell surface CD40 and secrete IL-12 as a consequence of ingesting CP. The prediction tested in Aim 2 is that a CD154 stimulus to lamina propria DCs results in the digestion of phagocytosed CP and epithelial cells and degradation of CP nucleic acids. These aims are selected because they address issues critical for understanding 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 Toxoplasma sp. The results will be important for immunodeficient humans chronically infected with the parasite.