HTLV Deregulation of CD40(L) in Cancer&Neurodegeneration

描述（由申请人提供）：细胞毒性T淋巴细胞（ctl）介导的细胞免疫反应在识别和清除人类T细胞嗜淋巴病毒I型（HTLV-I）感染的细胞中起着关键作用。基于ctl的细胞免疫功能异常被认为在与HTLV-I感染相关的白血病和神经炎性疾病的发生中起重要作用。尽管CTL反应效率低下可能导致成人T细胞白血病（ATL）的发展，但在htlv -l相关脊髓病/热带痉挛性麻痹（HAM/TSP）患者中，CTL细胞室过度活跃可能介导中枢神经系统（CNS）的炎症。这项研究的长期目标是确定htlv - 1介导的细胞免疫反应失调的分子机制，从而导致癌症和神经系统疾病。这一建议集中在CD40配体（CD40L）及其受体CD40在htlv -l感染的T细胞中的失调表达。CD40/ cd40l系统对于协调细胞和体液免疫反应至关重要。CD40L是一种共刺激分子，在活化的CD4+ T细胞上短暂表达，并与树突状细胞（dc）上的CD40结合，诱导功能成熟，从而有效激活抗病毒的CD8+ T细胞。本提案的目的是确定htlv - i介导的CD40和cd40l的失调机制，以及这些免疫介质失调对细胞免疫应答的功能影响。重点将是确定HTLV-I如何调节细胞信号通路和转录控制介导CD40和CD40L基因表达。本提案的具体目的是确定(1)htlv -i感染的T淋巴细胞中CD40转录激活的机制；(2) CD40对htlv -l感染T淋巴细胞活化、增殖及CD40L表达的影响；(3) HTLV-I和HTLV-I Tax对CD40L转录调控的影响；(4) CD40和CD40L表达失调对HTLV-I免疫应答的影响。这些研究的完成可能会导致免疫调节的治疗策略，这可能会预防白血病和/或神经炎症疾病。

DESCRIPTION (provided by applicant): The cellular immune response mediated by cytotoxic T lymphocytes (CTLs) plays a critical role in the identification and clearance of human T cell lymphotropic virus type I (HTLV-I)-infected cells. Functional abnormalities in CTL-based cellular immunity are thought to play a significant role in the genesis of leukemia and neuroinflammatory disease that is associated with HTLV-I infection. Whereas an inefficient CTL response likely contributes to the development of adult T cell leukemia (ATL), a hyperactive CTL compartment may mediate inflammation within the central nervous system (CNS) in individuals with HTLV-l-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The long-term goal of the proposed investigations is to define the molecular mechanisms of HTLV-I-mediated deregulation of the cellular immune response, which leads to cancer and neurologic disease. This proposal is centered on the deregulated expression of CD40 Ligand (CD40L) and its receptor CD40 in HTLV-l-infected T cells. The CD40/CD40Lsystem is critical for orchestrating both cellular and humoral immune responses. CD40L is a costimulatory molecule that is transiently expressed on activated CD4+ T cells and binds to CD40 on dendritic cells (DCs) and induces functional maturation allowing for efficient activation of antiviral CD8+ T cells. The objective of this proposal is to determine the mechanism underlying the HTLV-I-mediated deregulation of CD40 andCD40L, and the functional effects on the cellular immune response as a result of the deregulation of these immune mediators. The focus will be to determine how HTLV-I modulates cellular signaling pathways and transcriptional control mediating CD40 and CD40L gene expression. The specific aims of this proposal are to determine (1) the mechanism of CD40 transcriptional activation in HTLV-I-infected T lymphocytes; (2) the effects of CD40 on activation, proliferation and CD40L expression in HTLV-l-infected T lymphocytes; (3) the effects of HTLV-I and HTLV-I Tax on the transcriptional regulation of CD40L; and (4) the impact of deregulated expression of CD40 and CD40L on the immune response to HTLV-I. Completion of the proposed studies may lead to therapeutic strategies of immune modulation, which could prevent leukemia and/or neuroinflammatory disease.