CD4 T CELL ACTIVATION IN SIV INFECTED DISEASE RESISTANT SOOTY MANGABEYS

感染 SIV 的抗病乌白眉猴中 CD4 T 细胞的激活

• 批准号: 8357429
• 负责人: Aftab A. Ansari
• 金额: $ 7.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357429
• 关键词: Adult; Affect; Antigens; CD4 Positive T Lymphocytes; CREB1 gene; Cell Cycle; Cells; Cercocebus atys; Complex; Cyclin B; Cyclin-Dependent Kinases; Disease; Disease Resistance; EP300 gene; Functional disorder; Funding; Genes; Grant; Human; In Vitro; Infection; Interleukin-2; Lymphocyte; MCM6 gene; Macaca mulatta; Memory; National Center for Research Resources; Pathway interactions; Phosphotransferases; Primates; Principal Investigator; Regulation; Research; Research Infrastructure; Resistance; Resources; SIV; Source; T-Lymphocyte; United States National Institutes of Health; anergy; base; cancer immunotherapy; cost; cyclin D3; human FRAP1 protein; human PLK1 protein; memory CD4 T lymphocyte; novel therapeutics; peripheral blood

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project is aimed at delineating potential mechanistic differences of co-stimulatory pathways between CD4+ T cells from SIV disease susceptible rhesus macaques (RM) and SIV disease resistant sooty mangabeys (SM), based on the initial observation that adult sooty mangabey CD4+ T cells are resistant to in vitro anergy induction in contrast to rhesus macaques and human CD4+ T cells. Peripheral blood na¿ve and memory CD4+ T cells are obtained and stimulated in vitro to comparatively evaluate pathways including IL-2 synthesis regulation, CREB/CREM and p300 complex assembly, mTOR and cyclin dependent kinase regulation. These studies have highlighted a main difference between SIV infected SM and RM in the observation that SM central memory antigen specific T cells fail to upregulate GRAIL, the gene related to anergy in lymphocytes, unlike RM or human central memory cells, therefore preserving the potential of these cells to become potent effectors in the SM. In addition, an extension of previous studies that have identified dysfunction in polo-like kinases in CD4+ T cells from RM following SIV infection, recent microarray kinase analyses delineated several differences in cell cycle intermediates between TCR activated CD4 T cells from SM and RM. The most salient ones were a marked increase in Cyclin D3, E2F3, Cdc45/MCM6, Cyclin B and RAD17 in RM CD4+ T cells which affect both the afferent G1-S and the efferent S-G2 cell cycle transition steps. These studies are likely to open novel therapeutic alternatives based on selective blockade of specific kinases similar to experimental cancer immunotherapies.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供 该子项目的主要支持。 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源的子项目可能列出的总成本。 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 该项目旨在描绘来自 SIV 疾病易感恒河猴 (RM) 和抗 SIV 疾病的乌白眉猴 (SM) 的 CD4+ T 细胞之间共刺激途径的潜在机制差异，基于成年乌白眉猴 CD4+ T 细胞与恒河猴和人类外周血细胞相比，对体外无反应诱导具有抵抗力。对 ve 和记忆 CD4+ T 细胞进行体外刺激并比较评估途径，包括 IL-2 合成调节、CREB/CREM 和 p300 复合物组装、mTOR 和细胞周期蛋白依赖性激酶调节。这些研究强调了 SIV 感染的 SM 和获得的 RM 之间的主要区别。与 RM 或人类中枢记忆细胞不同，SM 中枢记忆抗原特异性 T 细胞无法上调 GRAIL（与淋巴细胞无反应性相关的基因），因此保留了这些细胞变得强大的潜力此外，之前的研究已发现 SIV 感染后 RM 中的 CD4+ T 细胞出现 Polo 样激酶功能障碍，最近的微阵列激酶分析描绘了 TCR 激活的 CD4 T 细胞之间细胞周期中间体的一些差异。 SM 和 RM 最显着的是 RM CD4+ T 细胞中的 Cyclin D3、E2F3、Cdc45/MCM6、Cyclin B 和 RAD17 显着增加。影响传入 G1-S 和传出 S-G2 细胞周期转换步骤。这些研究可能会基于选择性阻断特定激酶（类似于实验性癌症免疫疗法）开辟新的治疗替代方案。