CD40-CD154 Interactions in Cryptosporidial Immunity

描述(申请人提供)：微小隐孢子虫(CP)病因 携带艾滋病或CD154基因突变(X)的人的长期和严重感染 与高IgM相关的免疫缺陷，或XHIM)与 硬化性胆管炎和肝脏移植的需要。肺炎衣原体感染肠道 通常会被树突状细胞吞噬的上皮细胞 (DC)在固有层。这个应用程序背后的假设是 DC需要CD154信号来杀死被摄取的CP‘，如果没有 CD154-CD40信号，完整的CP到达肠系膜淋巴结(MLN)。这 假说解释了表达CD154的CD4T细胞的需求，以及 骨髓来源的CD4O+细胞，用于小鼠从CP感染中恢复。我们最近 表达卵清蛋白转基因T细胞受体的RAG-/-小鼠报告 (或细胞色素c)从CP感染中恢复表明一条非经典的途径 满足T细胞活化和CD154的表达，即 CP通关所必需的。初步研究将显示CP清除率 需要类H表达和CD4T细胞--这表明亲和力 对于自身的多肽和MHC是CP刺激的T细胞激活所必需的。 这一观察结果是目标1中检验的假设的基础：亲和力 对于CP，T细胞的激活需要自身的MHC复合体。我们 预测固有层DC上调其细胞表面CD40并分泌 IL-12作为摄入CP的结果。在目标2中测试的预测是 CD154对固有层DC的刺激导致吞噬细胞的消化 CP和上皮细胞以及CP核酸的降解。这些目标是 之所以被选中，是因为它们解决了对理解CP免疫力至关重要的问题 以及当感染没有被根除时产生的免疫病理学。 在CP感染中建立的机制可能与其他 重要的细胞内病原体，特别是微孢子虫和弓形虫 SP.这一结果将对慢性免疫缺陷患者具有重要意义。 感染了寄生虫。

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.