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

描述（由申请人提供）：树突状细胞（DC）是最有效的抗原呈递细胞，被认为是免疫系统的关键调节因子，连接正常免疫的刺激和抑制成分。虽然DC在原发性和继发性免疫应答方面具有良好的特征，但其在协调中枢和外周耐受性中的独特作用尚未完全阐明。越来越明显的是，DC维持耐受性的能力的失败可导致自身免疫性和/或炎性疾病。因此，人T细胞白血病病毒1型（HTLV-1）已被用作模式病原体，以探讨DC在病毒诱导的神经炎症中的作用。HTLV-1是两种免疫学上不同的疾病的病原体;成人T细胞白血病和HTLV-1相关的脊髓病/热带痉挛性下肢轻瘫（HAM/TSP）。HAM/TSP是一种慢性脱髓鞘疾病，在中枢神经系统中存在潜在的自身免疫性疾病，与多发性硬化症相似。HAM/TSP的进展特征在于慢性活化的CD 8+细胞毒性T淋巴细胞（CTL）的强烈增殖，其中90%对HTLV-1反式激活蛋白Tax具有特异性。一些临床观察表明，Tax特异性CTL应答充其量是无效的，并且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在神经发病机制上促进HAM/TSP。这种过度活化的CTL反应的起源（抗原呈递和共刺激）、引发（正常或缺陷）和质量（效应子与耗尽）仍不完全表征。DC对于HTLV-1神经发病机制特别重要，因为HAM/TSP的发展与DC的快速成熟相关。还已知HTLV-1在体外和HAM/TSP患者中感染DC，表明DC在HAM/TSP发病机制中起关键作用。本研究的假设是活化的DC持续呈递Tax肽至初始T细胞以及Tax对DC功能的调节在诱导和调节HAM/TSP特征性Tax特异性CTL应答中起重要作用。该假说的具体目标是：1）确定在DC直接感染和HTLV-1感染的T细胞交叉呈递过程中涉及的Tax呈递过程，涉及DC的生物学、生理学和免疫学功能的改变以及Tax特异性CTL应答的诱导;和2）利用离体分析来验证DC在前病毒载量和Tax表达的背景下在HAM/TSP患者中调节CD 8 + T细胞的抗病毒功效中的中心作用，疾病进展的两个主要风险因素。总的来说，这些研究将确定DC参与病毒相关的自身免疫性/神经炎性疾病，并强调在对病毒因子的获得性免疫过程中免疫细胞之间的关键功能相互作用。从这些研究中获得的额外信息将促进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。公共卫生相关性：拟议的研究与公共卫生有关，并将揭示有关树突状细胞调节的T细胞反应在复杂的自身免疫性/神经炎症性疾病，如HAM/TSP和多发性硬化症的重要信息。此外，这些研究的结果将揭示慢性病毒感染期间免疫细胞相互作用的动力学，如HTLV-1，HIV-1，肝炎病毒和单纯疱疹病毒。

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. PUBLIC HEALTH RELEVANCE: The proposed studies are relevant to public health and will reveal significant information concerning the dendritic cells-regulated T cell responses during complex autoimmune/neuroinflammatory diseases such as HAM/TSP and multiple sclerosis. Additionally the results of these studies will shed light on the dynamics of immune cell interactions during chronic viral infections such as HTLV-1, HIV-1, hepatitis virus and herpes simplex virus.