ANERGY, APOPTOSIS AND CD28 IN CD8+ T CELLS DURING AIDS

艾滋病期间 CD8 T 细胞的无能、凋亡和 CD28

• 批准号: 7032286
• 负责人: DOROTHY E. LEWIS
• 金额: $ 36.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032286
• 关键词: ANERGY; APOPTOSIS; CD28; CD8+; CELLS

Effector CD8+ T cells in HIV infection are responsible for initial viremia control, however, HIV-specific CTL memory cells are lost during disease progression by an unknown mechanism. Our data show that HIV+ patients contain HIV-specific CD8+ CD28dim cells which die by costimulation via monocytes. In addition, we found that HIV causes over-expression of the CD28 ligands (CD80 and CD86) in vitro, inducing CD28 loss and apoptosis of CD8+ T cells. These observations suggest a fundamental mechanism whereby CD8+ T cells capable of becoming memory HIV-specific CTL could be selectively lost during disease progression. To study this hypothesis we propose three aims. Aim 1 examines mechanisms for CD28 down-regulation and apoptosis. Using mixtures of CHO cell lines with defined levels of costimulatory ligands, CD80 or CD86, incubated with purified T cells, we will assess mechanisms responsible for Cd28 down-regulation and apoptosis. To examine the importance of HIV infection, we will mix autologous HIV-infected macrophages with T cells, examine CD80 and CD86 expression on the macrophages, as well as the effects of cell contact, soluble factors or cytokines released by the macrophages on CD28 down-regulation and apoptosis of the CD8+ T cells. Because little is known about molecular regulation of CD28 expression, Aim 2 will examine the down-regulation of the CD28 promoter by testing differential binding of NF-kBalpha and/or STAT-6 proteins, which will provide a molecular basis for prevention of CD28 loss. Aim 3 will develop potential therapeutic methods to increase antigen-specific memory CD8+ T cells in HIV. Using alloantigen as a model, we will modulate costimulation, activation conditions, timing, strength of signals, and cytokines. The most promising methods to increase memory CD8+ T cells will be used with CD8+ T cells from HIV-infected patients. Because CD8+ T cells are important for HIV control, these studies are important for development of immune intervention strategies and for vaccine design.

HIV感染中的效应者CD8+T细胞负责初始 然而，病毒血症的控制，HIV特异性的CTL记忆细胞在疾病期间丢失 一种未知机制的进展。我们的数据显示，HIV+患者含有 HIV特异性CD8+CD28dim细胞，通过单核细胞共刺激死亡。在……里面 此外，我们发现HIV导致CD28配体(CD80)的过度表达 和CD86)，诱导CD8+T细胞CD28丢失和凋亡。这些 观察表明CD8+T细胞能够 成为记忆HIV特异性CTL可能在疾病期间选择性丢失 进步。为了研究这一假设，我们提出了三个目标。AIM 1考试 CD28下调和细胞凋亡的机制。使用CHO细胞的混合物 共刺激配体CD80或CD86水平已确定的品系孵化 对于纯化的T细胞，我们将评估CD28的机制 下调与细胞凋亡。为了研究艾滋病毒感染的重要性，我们 将自体感染艾滋病毒的巨噬细胞与T细胞混合，检测CD80和 巨噬细胞上CD86的表达，以及细胞接触的影响， 巨噬细胞在CD28表面释放的可溶性因子或细胞因子 CD8+T细胞的下调和凋亡。因为我们知之甚少 关于CD28表达的分子调控，Aim 2将研究 通过检测CD28启动子的差异结合来下调CD28启动子 核因子-kBalpha和/或STAT-6蛋白，这将为 防止CD28丢失。AIM 3将开发潜在的治疗方法 增加HIV中抗原特异性记忆CD8+T细胞。使用同种异体抗原作为 模型中，我们将调制共刺激、激活条件、时间、强度 信号和细胞因子。最有希望增加CD8+T细胞记忆力的方法 细胞将与来自HIV感染患者的CD8+T细胞一起使用。因为CD8+T细胞 细胞对HIV控制很重要，这些研究对 发展免疫干预策略和疫苗设计。