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

超出所提供的空间。CD8 - T细胞在感染早期清除HIV至关重要。然而，在大多数人中，CD8 +记忆细胞有缺陷或死亡的速度加快。我们最近的研究表明，患者的单核细胞杀死来自患者和对照组的CD8 + T细胞，而对照组的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。其他研究表明，tnf - α和CD28激动作用（强B7信号、CD80或激动性CD28 Ab）均下调CD28表达，并可诱导与持续c-tel易位相关的死亡。由于mTNF被CD28激动作用上调，CD28激动性死亡的一个合理假设是通过TNFR1/TNFR2连接诱导，导致NFKB激活。因此，目的1将研究CD28激动信号导致细胞死亡的机制。由于CD28在通过死亡对CD28激动作用作出反应的T细胞上发生差异糖基化，并且CD28在死亡的ceu表面的位置发生改变，Aim 2将研究CD28细胞表面构象改变的机制，包括差异糖基化特征和活化诱导的CD28变化。我们将表征CD28上的糖，突变CD28上的五个糖基化位点，并研究活化ofT细胞前后CD28的糖基化模式和位置。将比较患者和对照T细胞的CD28糖基化差异或与强B7信号响应能力相关的定位模式。由于HIV的一个关键问题是无功能CD28”细胞的发展，Aim 3将使用同种异体抗原作为抗原，改变抗原呈递细胞、细胞因子、共刺激分子的类型，并研究CD4 + T细胞的作用，以开发增强CD8 + T细胞活力的方法。最有希望增加CD28 +记忆性CD8 + T细胞的方法将与来自HIV +患者的CD8 +细胞一起使用。这些实验对于通过治疗性疫苗控制HIV很重要，因为需要提高CD28表达和CD8 + T细胞存活的策略，以增强其在体内的长期能力。网站性能 ======================================== 节结束 ===========================================

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===========================================