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是由CD4和CD8 T细胞消除病毒感染细胞或有效延缓病毒复制的能力控制的。这对于诸如HIV、CMV或HCV等从未被免疫系统清除的持久性病毒尤其重要。本提案描述了旨在理解引导T细胞分化和功能的中央控制机制的实验。Foxo转录因子受氧化应激、生长因子（如胰岛素）丰度、营养可用性或炎症等生理条件的差异调节。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CD8细胞毒性T细胞感染后的扩增和激活状态。此外，Foxo1的缺失促进了CD4中枢记忆前体细胞和CD4滤泡辅助细胞产生IL-21的出现。这些结果结合对HIV精英控制患者Foxo3活性缺陷的观察，揭示了该转录因子模块对免疫系统施加的核心和深远影响。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，并大规模分析它们对基因表达编程的控制。这一结果将对长期共同进化的病毒性疾病，如HIV、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.