CD40-CD154 Interactions in Cryptosporidial Immunity

描述（由申请人提供）：隐孢子虫（CP）引起 艾滋病或CD 154基因突变的人类长期和严重感染（X 与高IgM相关的免疫缺陷，或XHIM）， 硬化性胆管炎和需要肝脏移植CP感染肠道 上皮细胞通常会被树突细胞吞噬， (DC)在固有层中。本申请的基本假设是， “DC需要CD 154信号来杀死摄入的CP”，如果没有 CD 154-CD 40信号，完整CP到达肠系膜淋巴结（MLN）。这 该假说解释了表达CD 154的CD 4 T细胞的需求， 骨髓来源的CD 4 O+细胞，用于小鼠从CP感染中恢复。我们最近 报道表达卵清蛋白转基因T细胞受体的RAG-/-小鼠 (or细胞色素c）从CP感染中恢复表明， 足以激活T细胞和表达CD 154， CP许可所需的。初步研究表明， 需要H类表达以及CD 4 T细胞-这表明亲和力 对于自身肽加上MHC是CP刺激的T细胞活化所需的。 这一观察结果是目标1中检验的假设的基础： 对于自身MHC复合物是响应CP的T细胞活化所必需的。我们 预测固有层DCs上调其细胞表面CD 40并分泌 IL-12是摄入CP的结果。目标2中测试的预测是， CD 154刺激固有层DC导致吞噬的 CP和上皮细胞以及CP核酸的降解。这些目的是 之所以选择它们，是因为它们解决了理解CP免疫的关键问题 以及感染未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疾病有关。 重要的细胞内病原体，特别是微孢子虫和弓形虫 这一结果对免疫缺陷的人类长期免疫具有重要意义。 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.