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: 7394326
• 负责人: DOROTHY E. LEWIS
• 金额: $ 34.95万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 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/7394326
• 关键词: Acquired Immunodeficiency Syndrome; Alloantigen; Antigen-Presenting Cells; Antigens; Apoptosis; Autologous; Binding; Biological Assay; CD28 gene; CD4 Positive T Lymphocytes; CD80 gene; CD8B1 gene; Cell Line; Cell physiology; Cells; Chinese Hamster Ovary Cell; Condition; Controlled Study; Cytokine Activation; Cytokine Signaling; DNA; Data; Detection; Development; Disease Progression; Down-Regulation; Environment; HIV; HIV Infections; Hand; Immune; In Vitro; Incubated; Infection; Interleukin-2; Interleukin-4; Intervention; Ligands; Memory; Methods; Modeling; Molecular; Nuclear Protein; Nuclear Proteins; Numbers; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phosphorylation; Population; Prevention; Production; Proteins; Regulation; Signal Transduction; System; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Time; Vaccine Design; Viremia; anergy; base; cytokine; macrophage; monocyte; plasma protein Z; prevent; promoter; research study; restoration

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+CD28 m cells which die by costimulation via monocytes. hi addition, we found that HFV 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 1examines mechanisms for CD28 down-regulation and apoptosis. Using mixtures of CHO cell lineswith 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 CDS 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- kBa and/or STAT-6 proteins, which will provide a molecular basis for prevention of CD28 loss. Ann 3 willdevelop 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 CD8+ T 细胞负责初始病毒血症控制，然而，HIV 特异性 CTL 记忆细胞在疾病进展过程中因未知机制而丢失。我们的数据显示 HIV+ 患者 含有 HIV 特异性 CD8+CD28 m 细胞，这些细胞通过单核细胞的共刺激而死亡。您好，此外，我们发现 HFV 在体外引起 CD28 配体（CD80 和 CD86）过度表达，诱导 CD28 丢失和 CD8+ 凋亡 T细胞。这些观察结果表明 CD8+ T 细胞能够成为记忆的基本机制 HIV特异性CTL可能在疾病进展过程中选择性丢失。为了研究这个假设，我们提出了三个 目标。目标 1 检查 CD28 下调和细胞凋亡的机制。使用 CHO 细胞系的混合物 确定水平的共刺激配体 CD80 或 CD86，与纯化的 T 细胞一起孵育，我们将评估机制 负责 CD28 下调和细胞凋亡。为了检验 HIV 感染的重要性，我们将混合 使用 T 细胞检测自体 HIV 感染的巨噬细胞，检查巨噬细胞上的 CD80 和 CD86 表达，如 以及细胞接触、巨噬细胞释放的可溶性因子或细胞因子对 CD28 下调的影响 CDS T 细胞的调节和凋亡。因为对 CD28 的分子调控知之甚少 表达，目标 2 将通过测试 NF- 的差异结合来检查 CD28 启动子的下调 kBa 和/或 STAT-6 蛋白，这将为预防 CD28 丢失提供分子基础。安3将开发 增加 HIV 中抗原特异性记忆 CD8+ T 细胞的潜在治疗方法。使用同种异体抗原作为 模型中，我们将调节共刺激、激活条件、时间、信号强度和细胞因子。最 增加记忆 CD8+ T 细胞的有前途的方法将与来自 HIV 感染者的 CD8+ T 细胞一起使用。 由于 CD8+ T 细胞对于 HIV 控制很重要，因此这些研究对于免疫系统的发展也很重要 干预策略和疫苗设计。