A molecular basis for control of T cell memory

描述(由申请人提供)：急性和持续性病毒感染的进展部分取决于CD4和CD8 T细胞清除病毒感染细胞或有效抑制病毒复制的能力。这对于那些从未被免疫系统清除的持久性病毒，如艾滋病毒、巨细胞病毒或丙型肝炎病毒尤其重要。这项建议描述了旨在了解引导T细胞分化和功能的中央控制机制的实验。FOXO转录因子受生理条件的不同调控，如氧化应激、生长因子(如胰岛素)的丰度、营养的可获得性或炎症。整合这些信息，它们促进或限制控制细胞存活、静止、DNA修复和新陈代谢的基因表达程序，并直接控制高度专业化的功能，包括：IL-7受体、CTLA-4和iCos。特别是，提供的初步数据表明，FOXO转录因子控制感染后CD8细胞毒性T细胞的扩增和激活状态。此外，Foxo1的缺失促进了CD4中央记忆前体细胞的出现，以及CD4滤泡辅助细胞能够产生IL-21。这些结果与HIV精英控制者患者Foxo3活性缺陷的观察相结合，揭示了这个转录因子模块对免疫系统施加的中心和深远影响。我们建议深入分析Foxo1和Foxo3转录因子在病毒感染的进展和清除中的作用，并对它们对基因表达编程的控制进行大规模分析。这些结果将对长期共同进化的病毒疾病的进展产生直接影响，如艾滋病毒、疱疹病毒和丙型肝炎病毒。

DESCRIPTION (provided by applicant): The progression of acute and persistent viral infections is governed, in part, by the ability of CD4 and CD8 T cells to eliminate virus-infected cells or effectively retard viral replication. This is especially important for persistent viruses uch as HIV, CMV, or HCV that are never cleared by the immune system. This proposal describes experiments designed to understand a central control mechanism guiding T cell differentiation and function. Foxo transcription factors are differentially regulated by physiological conditions such as oxidative stress, abundance of growth factors (such as insulin), nutrient availability, or inflammation. Integrating this information, they promote or restrict programs of gene expression that govern cellular survival, quiescence, DNA repair, and metabolism, and they directly control highly specialized functions including: the IL-7 receptor, CTLA-4, and Icos. In particular, preliminary data presented demonstrate that Foxo transcription factors control the expansion and activation status of CD8 cytotoxic T cells post-infection. In addition, the absence of Foxo1 promotes the appearance of CD4 central memory precursor cells, and CD4 follicular helper cells able to produce IL-21. These results combined with the observation that HIV elite controller patients have a deficit in Foxo3 activity, reveal the central and profound influence that this transcription factor module exerts on the immune system. We propose an in depth analysis of Foxo1 and Foxo3 transcription factors in the progression and clearance of virus infections, and a large-scale analysis of their control over the programming of gene expression. The results will have direct implications for the progression of long co-evolved viral diseases such as HIV, Herpes, and Hepatitis C virus.