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受CD 4和CD 8 T细胞清除病毒感染细胞或有效延缓病毒复制的能力控制。这对于HIV、CMV或HCV等持久性病毒尤其重要，这些病毒从未被免疫系统清除。该提案描述了旨在了解指导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如氧化应激、生长因子（如胰岛素）丰度、营养物质可用性或炎症的差异调节。整合这些信息，它们促进或限制控制细胞存活、静止、DNA修复和代谢的基因表达程序，并且它们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，初步数据表明，Foxo转录因子控制的CD 8细胞毒性T细胞感染后的扩增和活化状态。此外，Foxo 1的缺乏促进了CD 4中央记忆前体细胞和能够产生IL-21的CD 4滤泡辅助细胞的出现。这些结果结合HIV精英控制者患者Foxo 3活性缺陷的观察，揭示了这种转录因子模块对免疫系统产生的重要而深远的影响。我们提出了一个深入的分析Foxo 1和Foxo 3转录因子在病毒感染的进展和清除，和大规模的分析他们的控制编程的基因表达。这些结果将对长期共同进化的病毒性疾病如艾滋病毒、疱疹和丙型肝炎病毒的进展产生直接影响。

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.