CD4 T CELL ACTIVATION IN SIV INFECTED DISEASE RESISTANT SOOTY MANGABEYS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 本项目旨在描述SIV疾病易感恒河猴(RM)和SIV抗病黑猩猩(SM)的CD4+T细胞之间潜在的共刺激途径的机制差异，初步观察到成人红斑猕猴的CD4+T细胞与恒河猴和人类的CD4+T细胞相比，对体外无能诱导具有抵抗性。采集外周血中的中性和记忆性CD4+T细胞，体外刺激，比较研究IL-2合成调节、CREB/CREM和p300复合体组装、mTOR和细胞周期蛋白依赖性激酶调节等途径。这些研究突出了SIV感染的SM和RM之间的主要区别，即SM中央记忆抗原特异性T细胞不能上调GRAIL，与RM或人类中央记忆细胞不同，GRAIL是与淋巴细胞无能相关的基因，因此保留了这些细胞成为SM有效效应者的潜力。此外，作为先前研究的延伸，在SIV感染后，SM和RM的CD4+T细胞中存在类似Polo的蛋白激酶功能障碍，最近的微阵列分析揭示了SM和RM的TCR激活的CD4T细胞在细胞周期中间产物上的几个差异。其中最显著的是RMCD_4+T细胞中Cyclin D3、E2F3、CDC45/MCM6、Cyclin B和RAD17的表达显著增加，这对传入的G1-S和传出的S-G2细胞周期转换步骤都有影响。这些研究可能会开辟新的治疗方案，基于选择性阻断特定的激酶，类似于实验性的癌症免疫疗法。

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.