CD4 T CELL ACTIVATION IN SIV INFECTED DISEASE RESISTANT SOOTY MANGABEYS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。因此，我们从外周血中获取并在体外刺激NK细胞和记忆性CD4+T细胞，以比较研究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。这些研究最近强调了SIV感染SM和RM之间的主要区别，观察到SM中央记忆抗原特异性T细胞不能上调GRAIL，这是与淋巴细胞无能相关的基因，不同于RM或人类中央记忆细胞，因此保留了这些细胞在SM猴子中成为强大效应器的潜力。 此外，之前的研究发现SIV感染后恒河猴的CD4+T细胞中的Polo-like Kinase功能障碍，最近的微阵列激酶分析揭示了来自SM和RM的TCR激活的CD4T细胞在细胞周期中间产物方面的几个差异。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。这些变化可能促进T细胞的激活、更新和凋亡增加，而在SM中，当比较SIV感染前后的CD4T细胞时，这些变化并不明显。 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. Hence 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 recently 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 monkey. In addition, an extension of previous studies that have identified dysfunction in polo-like kinases in CD4+ T cells from rhesus macaques 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 alterations are likely to promote increased T cell activation, turnover and apoptosis whereas these changes were not seen when comparing CD4 T cells from before and after SIV infection in SM. These studies are likely to open novel therapeutic alternatives based on selective blockade of specific kinases similar to experimental cancer immunotherapies.