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

超出所提供的空间。 CD 8 ~+ T细胞对于HIV感染早期的清除至关重要。然而，在大多数人中，CD 8+记忆细胞有缺陷或死亡率增加。我们最近的工作表明，患者单核细胞杀死患者和对照组的CD 8 + T细胞，对照单核细胞杀死患者的CD 8 + T细胞，这表明HIV中CD 8 + T细胞的死亡不是抗原特异性的。其他研究表明，TNF-α和CD 28激动剂（强B7信号、CD 80或激动性CD 28 Ab）均下调CD 28表达，并可诱导与持续c-tel易位相关的死亡。因为mTNF被CD 28激动上调，所以CD 28激动性死亡的合理假设是通过TNFR 1/TNFR 2连接诱导，导致NF κ B活化。因此，目的1将研究导致细胞死亡的CD 28激动性信号传导的机制。 由于CD 28在对CD 28激动反应的T细胞上通过死亡而差异糖基化，并且CD 28在死亡的细胞表面上的位置被改变，因此Aim 2将检查CD 28细胞表面构象改变的机制，包括差异糖基化特征和CD 28的活化诱导的变化。我们将对CD 28上的糖进行表征，突变CD 28上的五个糖基化位点，并研究T细胞活化前后CD 28的糖基化模式和位置。将比较患者和对照T细胞的差异CD 28糖基化或与对强B7信号的应答能力相关的位置模式。 由于HIV中的一个关键问题是无功能的CD 28+细胞的发育，Aim 3将使用同种异体抗原作为抗原，并改变抗原呈递细胞、细胞因子、共刺激分子的类型，并研究CD 4 + T细胞的作用，以开发增强CD 8 + T细胞活力的方法。增加CD 28+记忆性CD 8 + T细胞的最有希望的方法将用于来自HIV +患者的CD 8+细胞。这些实验对于通过治疗性疫苗控制HIV是重要的，因为需要策略来增强CD 28表达和CD 8 + T细胞的存活以增强其在体内的长期能力。性能现场=

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