CD4 T CELL ACTIVATION IN SIV INFECTED DISEASE RESISTANT SOOTY MANGABEYS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本项目的目的是描绘来自SIV疾病易感恒河猴（RM）和SIV疾病抗性白眉猴（SM）的CD 4 + T细胞之间的共刺激通路的潜在机制差异，基于与恒河猴和人CD 4 + T细胞相比，成体白眉猴CD 4 + T细胞对体外无反应性诱导具有抗性的初步观察。外周血钠获得原始和记忆性CD 4 + T细胞，并在体外刺激以比较评估途径，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RM之间的主要差异，即SM中央记忆抗原特异性T细胞不能上调GRAIL（淋巴细胞中与无反应性相关的基因），这与RM或人中央记忆细胞不同，因此保留了这些细胞成为SM中有效效应物的潜力。此外，扩展以前的研究，已经确定功能障碍的polo样激酶在CD 4 + T细胞从RM后SIV感染，最近的微阵列激酶分析描绘了几个不同的TCR激活的CD 4 T细胞之间的细胞周期中间体从SM和RM。最显著的变化是RM CD 4 + T细胞中Cyclin D3、E2 F3、Cdc 45/MCM 6、Cyclin B和RAD 17的显著增加，其影响传入G1-S和传出S-G2细胞周期转换步骤。这些研究可能会开辟新的治疗方案的基础上选择性阻断特定的激酶类似于实验性癌症免疫疗法。

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.