Define the role of dendritic cells in HTLV-1 associated neuroinflammatory disease

描述(申请人提供)：树突状细胞(DC)是最强大的抗原提呈细胞，被认为是免疫系统的关键调节细胞，连接正常免疫的刺激和抑制成分。虽然树突状细胞在原发和继发免疫反应方面有很好的特点，但它们在协调中枢和外周耐受方面的独特作用还没有完全被描述。越来越明显的是，DC维持耐受性的能力失败会导致自身免疫性和/或炎症性疾病。因此，以人类T细胞白血病病毒1型(HTLV-1)为模型病原体，探讨树突状细胞在病毒诱导的神经炎症中的作用。HTLV-1是两种免疫学上截然不同的疾病的病原体；成人T细胞白血病和HTLV-1相关性脊髓病/热带痉挛麻痹(HAM/TSP)。HAM/TSP是一种慢性脱髓鞘疾病，其基础是中枢神经系统的自身免疫状态，类似于多发性硬化症。HAM/TSP的进展特征是慢性激活的CD8+细胞毒性T淋巴细胞(CTL)的强烈增殖，其中90%是HTLV-1反式激活蛋白TAX的特异性细胞。一些临床观察表明，TAX特异性CTL反应充其量是无效的，实际上可能通过与神经元抗原交叉反应或通过旁观者细胞损伤而有害地促进HAM/TSP的神经发病。这种高度激活的CTL反应的起源(抗原提呈和共刺激)、启动(正常或缺陷)和质量(效应者与疲劳者)仍未完全确定。DC在HTLV-1神经发病机制中具有特别重要的作用，因为HAM/TSP的发展与DC的快速成熟有关。HTLV-1在体外和HAM/TSP患者体内均可感染DC，提示DC在HAM/TSP的发病机制中起重要作用。这一假说认为，激活的DC向初始T细胞持续递呈Tax肽和Tax对DC功能的调节在HAM/TSP的Tax特异性CTL应答特性的诱导和调节中起重要作用。针对这一假说的具体目的将1)定义在DC直接感染和HTLV-1感染的T细胞的交叉呈递过程中，DC的生物、生理和免疫功能的变化以及Tax特异性CTL反应的诱导；2)在疾病进展的两个主要风险因素-前病毒负载和Tax表达的背景下，利用体外分析来验证DC在调节HAM/TSP患者CD8+T细胞抗病毒效果方面的核心作用。总的来说，这些研究将确定树突状细胞在病毒相关自身免疫性/神经炎性疾病中的参与，并强调免疫细胞在对病毒制剂的获得性免疫过程中的关键功能相互作用。从这些研究中获得的更多信息将有助于新型疫苗和治疗措施的转化研究开发，以预防和/或治疗HTLV-1诱导的神经炎性疾病以及其他病因的类似疾病。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are the most potent antigen presenting cells and are recognized as key regulators of the immune system, linking both stimulatory and inhibitory components of normal immunity. While DCs are well characterized with respect to primary and secondary immune responses, their unique role in coordinating central and peripheral tolerance is not fully delineated. It is increasingly evident that the failure of DCs' ability to maintain tolerance can lead to autoimmune and/or inflammatory diseases. Consequently, human T cell leukemia virus type 1 (HTLV-1) has been used as a model pathogen to explore the role of DCs in virus- induced neuroinflammation. HTLV-1 is the etiologic agent of two immunologically distinct diseases; adult T cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic demyelinating disease with underlying autoimmune condition in the central nervous system with similarities to multiple sclerosis. The progression of HAM/TSP is characterized by an intense proliferation of chronically activated CD8+ cytotoxic T lymphocytes (CTLs), 90% of which are specific for the HTLV-1 transactivator protein Tax. Several clinical observations suggest that Tax-specific CTL response is at best ineffective and may actually be detrimentally contributing to the neuropathogenesis of HAM/TSP by cross-reacting with neuronal antigens or through bystander cell damage. The genesis (antigen presentation and costimulation), priming (normal or defective), and quality (effector versus exhausted) of this hyperactivated CTL response remain incompletely characterized. DCs are of particular importance with respect to HTLV-1 neuropathogenesis as the development of HAM/TSP is associated with rapid maturation of DCs. HTLV-1 is also known to infect DCs both in vitro and in HAM/TSP patients suggesting that DCs play a critical role in HAM/TSP pathogenesis. The HYPOTHESIS of this proposal is that continuous presentation of Tax peptide by activated DCs to naive T cells and modulation of DC functions by Tax play important role in the induction and regulation of Tax-specific CTL response characteristic of HAM/TSP. The SPECIFIC AIMS to this hypothesis will 1) define the process involved in Tax presentation during direct DC infection and cross-presentation from HTLV-1-infected T cells with respect to the alterations in the biologic, physiologic, and immunologic function of DCs and induction of Tax-specific CTL response; and 2) utilize ex vivo analyses to validate the central role of DCs in regulating antiviral efficacy of CD8+ T cells in HAM/TSP patients within the context of proviral load and Tax expression, the two major risk factors in disease progression. Collectively, these studies will define the involvement of DCs in a virus-associated autoimmune/neuroinflammatory disease and highlight critical functional interactions among immune cells during acquired immunity to a viral agent. Additional information derived from these studies will facilitate the translational research development of novel vaccine and therapeutic initiatives to prevent and/or treat HTLV-1-induced neuroinflammatory disease as well as similar diseases of other etiologies.