CD8 Tcells and Tissue E-cadherin in Host Defense Against Oral Candidiasis in HIV

描述（由申请人提供）：口咽念珠菌病（OPC）是HIV感染最常见的口腔表现。病原体白色念珠菌是一种机会致病菌，也是口腔黏膜常见的正常菌群。Th1型CD4+细胞介导的免疫被认为是OPC的主要宿主防御机制。然而，这种宿主反应在CD4+ T细胞数量减少的HIV患者中是微不足道的。相反，在CD4+ T细胞减少的情况下，需要其他针对白色念珠菌的次级宿主防御。阐明在缺乏足够数量CD4+ T细胞的情况下有效运作的口服抗念珠菌免疫防御机制，对于开发新的免疫疗法，增强HIV+个体对OPC的保护性免疫反应至关重要。因此，我们的研究暗示CD8+ T细胞在宿主防御OPC中起着假定的“次要”作用。在这一作用中，CD8+效应T细胞被招募到口腔黏膜，并在整个固有层和上皮中迁移，在必要时提供效应功能。然而，在OPC中，它们在基底外侧上皮/固有层界面积聚，并与上皮黏附分子e -钙粘蛋白表达减少相关，e -钙粘蛋白促进上皮内CD8+ T细胞的迁移。我们假设CD8+ T细胞在口腔中具有抗念珠菌活性，但最佳效应功能通常被念珠菌介导的组织e -钙粘蛋白畸变所排除，而这种畸变可以通过治疗来逆转/恢复。因此，本项目将重点研究口腔内CD8+ T细胞抗念珠菌宿主防御机制，我们认为这可能是一种新的免疫机制，受生物体和抗逆转录病毒或免疫疗法成分的影响。在项目完成后，我们希望证明这些“次级”类型的免疫反应如何对口腔中的念珠菌起作用，它们如何以及为什么无效，以及现有的抗逆转录病毒和免疫疗法如何不仅与这些“次级”反应联系起来，而且如何进一步利用它们来控制艾滋病毒疾病中的OPC。

DESCRIPTION (provided by applicant): Oropharyngeal candidiasis (OPC) is the most common oral manifestation of HIV infection. The causative agent, Candida albicans, is both an opportunistic pathogen and common normal flora of the oral mucosa. Th1- type CD4+ cell-mediated immunity is considered the predominant host defense mechanism against OPC. However, this host response is negligible and irrelevant in HIV patients with reduced CD4+ T cell numbers. Instead other secondary host defenses against C. albicans are required under reduced CD4+ T cell conditions. The elucidation of oral anti-Candida immune defense mechanisms that can effectively operate in the absence of adequate numbers of CD4+ T cells is crucial for the development of novel immunotherapies that will enhance protective immune responses to OPC in HIV+ individuals. Accordingly, our studies have implicated CD8+ T cells as playing a putative 'secondary' role in host defense against OPC. In this role, CD8+ effector T cells are recruited into the oral mucosa and migrate throughout the lamina propria and epithelium, providing effector function where necessary. In OPC, however, they accumulate at the basolateral epithelial/lamina propria interface and correlates with a reduction in epithelial expression of the adhesion molecule, E-cadherin, which facilitates migration of CD8+ T cells in the epithelium. We hypothesize that CD8+ T cells have anti- Candida activity in the oral cavity, but optimal effector function is often precluded by Candida-mediated aberrations of tissue E-cadherin that can be reversed/restored therapeutically. Hence this project will focus on the uncharacterized anti-Candida host defense mechanisms by CD8+ T cells in the oral cavity, that we believe may be a novel immune mechanism and influenced by both the organism and components of antiretroviral or immuno therapies. Following completion of the project we expect to demonstrate how these 'secondary' type of immune responses function against Candida in the oral cavity, how and why they can be ineffective, and how existing antiretroviral and immune therapies not only link to these 'secondary' responses, but also how they can be exploited further to control OPC in HIV disease.