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反应方面具有很好的特征，但它们在协调中枢和外周耐受方面的独特作用尚未得到充分描述。越来越明显的是，dc维持耐受性能力的失败可导致自身免疫性和/或炎症性疾病。因此，人类T细胞白血病病毒1型（HTLV-1）被用作模型病原体来探索dc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；成人T细胞白血病和htlv -1相关脊髓病/热带痉挛性麻痹（HAM/TSP）。HAM/TSP是一种慢性脱髓鞘疾病，伴有中枢神经系统潜在的自身免疫性疾病，与多发性硬化症相似。HAM/TSP的进展以慢性活化CD8+细胞毒性T淋巴细胞（ctl）的强烈增殖为特征，其中90%是HTLV-1反激活蛋白Tax特异性的。一些临床观察表明，税收特异性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对HAM/TSP的神经发病机制产生不利影响。这种过度激活的CTL反应的发生（抗原呈递和共刺激）、启动（正常或有缺陷）和质量（效应与耗尽）仍未完全表征。由于HAM/TSP的发展与dc的快速成熟有关，因此dc在HTLV-1神经发病机制中具有特别重要的意义。HTLV-1在体外和HAM/TSP患者中也会感染dc，这表明dc在HAM/TSP发病机制中起关键作用。本研究的假设是，激活的DC持续向幼稚T细胞呈递Tax肽，并通过Tax调节DC功能，在HAM/TSP的税收特异性CTL反应特征的诱导和调节中发挥重要作用。这一假设的具体目的是：1)定义直接DC感染和htlv -1感染的T细胞交叉呈递DC时的Tax呈递过程，涉及DC的生物、生理和免疫功能的改变以及诱导Tax特异性CTL反应；2)利用离体分析验证dc在调节HAM/TSP患者CD8+ T细胞抗病毒功效中的核心作用，这是疾病进展的两个主要危险因素。总的来说，这些研究将确定dc与病毒相关的自身免疫/神经炎症疾病的关系，并强调在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更多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诱导的神经炎症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.