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: 6373418
• 负责人: DOROTHY E. LEWIS
• 金额: $ 31.55万
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373418
• 关键词: AIDS; CD28 molecule; HIV infections; anergy; apoptosis; cell mediated lymphocytolysis test; clinical research; cytotoxic T lymphocyte; human subject; leukocyte activation /transformation; macrophage; molecular pathology; nuclear factor kappa beta; nuclear runoff assay; tissue /cell culture

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CD 8 + T细胞负责初始免疫应答。 然而，HIV特异性CTL记忆细胞在疾病期间丢失， 以未知的机制进展。我们的数据显示，艾滋病毒+患者含有 HIV特异性CD 8 + CD 28 dim细胞，通过单核细胞的共刺激而死亡。在 另外，我们发现HIV引起CD 28配体（CD 80）的过度表达 和CD 86），诱导CD 8 + T细胞的CD 28损失和凋亡。这些 观察表明，CD 8 + 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 进展为了研究这个假设，我们提出了三个目标。目标1检查 CD 28下调和细胞凋亡的机制。使用CHO细胞的混合物 具有确定水平的共刺激配体CD 80或CD 86的细胞系， 与纯化的T细胞，我们将评估机制负责镉28 下调和凋亡。为了研究艾滋病毒感染的重要性，我们 将自体HIV感染的巨噬细胞与T细胞混合，检查CD 80， 巨噬细胞上的CD 86表达，以及细胞接触的影响， CD 28上巨噬细胞释放的可溶性因子或细胞因子 CD 8 + T细胞的下调和凋亡。因为我们所知甚少 关于CD 28表达的分子调控，Aim 2将研究 通过测试CD 28启动子的差异结合来下调CD 28启动子。 NF-kB α和/或STAT-6蛋白，这将提供分子基础， 防止CD 28丢失。目标3将开发潜在的治疗方法， 增加HIV中抗原特异性记忆CD 8 + T细胞。使用同种异体抗原作为 模型，我们将调节共刺激，激活条件，时机，强度 信号和细胞因子。最有前途的方法来增加记忆CD 8 + T 细胞将与来自HIV感染患者的CD 8 + T细胞一起使用。因为CD 8 + T 细胞对艾滋病毒控制很重要，这些研究对 免疫干预策略的制定和疫苗设计。