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: 6869346
• 负责人: DOROTHY E. LEWIS
• 金额: $ 31.88万
• 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/6869346
• 关键词: ANERGY; APOPTOSIS; CD28; CD8+; CELLS

EXCEED THE SPACE PROVIDED. CD8 ¿ T cells are essential for HIV clearance early in infection. However, in most people, CD8 + memory cells are defective or die at an increased rate. Our recent work shows that patient monocytcs kill CD8 + T cells from both patients and controls and that control monocytes kill patient CD8 ¿ T cells, suggesting that the death of CD8 + T cells in HIV is NOT antigen specific. Other work shows that both TNF-alpha and CD28 agonism (strong B7 signals, CD80, or agonistic CD28 Ab) downregulat¿ CD28 expression and can induce death associated with sustained c-tel translocation. Because mTNF is upregulated by CD28 agonism, a plausible hypothesis for CD28 agonistic death is induction via TNFR1/TNFR2 ligation, leading to NFKB activation. Aim 1 will therefore examine mechanisms of CD28 agonistic signaling that leads to cell death. Because CD28 is differentially glycosylated on T cells that respond to CD28 agonism by dying, and the location of CD28 on the surface of ceUs that die is altered, Aim 2 will examine mechanisms for alteration of CD28 cell surface conformation, including differential glycosylation characteristics and activation-induced changes of CD28. We will characterize sugars on CD28, mutate the five glycosylation sites in CD28, and study glycosylation patterns and location of CD28 before and after activation ofT cells. Patient and control T cells will be compared as to differential CD28 glycosylation or location patterns related to the ability to respond to strong B7 signals. Because a key problem in HIV is the development of non-functional CD28" cells, Aim 3 will use alloantigen as antigen and vary the type of antigen presenting cells, cytokines, costimulatory molecules, and investigate the role of CD4 + T cells to develop ways to enhance CD8 + T cell viability. The most promising methods that increase CD28 + memory CD8 + T cells wiU be used with CD8 + cells from HIV + patients. These experiments are important for HIV control by therapeutic vaccines because of strategies needed to enhance CD28 expression and survival of CD8 + T cells for enhancement of their long-term capabilities in vivo. PERFORMANCE SITE ========================================Section End===========================================

超出提供的空间。CD8T细胞对于HIV感染早期清除是必不可少的。然而，在大多数人中，CD8+记忆细胞有缺陷或以更快的速度死亡。我们最近的工作表明，患者单核细胞杀死患者和对照组的CD8+T细胞，而对照单核细胞杀死患者的CD8？T细胞，这表明HIV中CD8+T细胞的死亡不是抗原特异性的。其他工作表明，肿瘤坏死因子-α和CD28激动剂(强B7信号，CD80或激动型CD28抗体)均下调CD28的表达，并可诱导与持续c-tel易位相关的死亡。由于mtnf被CD28激动剂上调，CD28激动性死亡的合理假说是通过连接TNFR1/TNFR2，导致NFKB激活。因此，目标1将研究导致细胞死亡的CD28激动型信号转导机制。由于CD28在通过死亡对CD28激动剂作出反应的T细胞上被差异糖基化，并且CD28在死亡的CEU表面的位置发生改变，因此AIM 2将研究CD28细胞表面构象改变的机制，包括CD28的差异糖基化特征和激活诱导的变化。我们将对CD28上的糖进行表征，突变CD28上的5个糖基化位点，并研究CD28在细胞激活前后的糖基化模式和位置。患者和对照T细胞将在CD28糖基化或定位模式方面进行比较，这些模式与对强烈B7信号的反应能力有关。由于艾滋病病毒的一个关键问题是无功能的CD2 8“细胞的发展，Aim 3将使用同种异体抗原作为抗原，改变抗原提呈细胞、细胞因子、共刺激分子的类型，并研究CD4+T细胞的作用，以开发提高CD8+T细胞活性的方法。最有希望增加CD2 8+记忆CD8+T细胞的方法将用于HIV+患者的CD8+细胞。这些实验对治疗性疫苗控制艾滋病毒很重要，因为需要提高CD2 8+T细胞的表达和存活率，以增强其在体内的长期能力。Performance Site========================================Section End===========================================