Control of CD8+ Effector T Cell Differentiation

描述(申请人提供)：细胞介导的免疫对于宿主防御所有种类的病原体和经历了癌变的细胞至关重要。接种或增强T淋巴细胞介导的细胞免疫的策略已经非常无效，可能是因为我们对建立和维持T细胞效应器功能和记忆的机制了解有限。这项建议调查了两个T-box家族转录因子如何促进细胞免疫的形成。Eomesodermin和T-bet冗余地确保CD8+T细胞成为细胞毒效应细胞，但它们在正常和异常CD8+T细胞分化中似乎也相互对立。这使得这两个转录因子在末端分化和自我更新的相反需求之间形成了可调节的平衡。该项目的具体目标将解决EOMES如何以及何时在存储器T单元编程中发挥作用。这些目标还将解决eome在记忆细胞中的主要作用是否在一组独特的基因上，或者eome是否通过与T-bet在它们共同调节的位点上相互作用来控制CD8+T细胞的记忆。这一建议的三个具体目标的成功实现将为免疫反应中的基因诱导和细胞分化机制提供新的见解。预计这些研究将为我们提供新的策略来防御各种传染病，这些传染病是我们CD8+T细胞反应的焦点。

DESCRIPTION (provided by applicant): Cell-mediated immunity is critical for host defense against all classes of pathogens and cells that have undergone cancerous transformation. Strategies to vaccinate or potentiate T lymphocyte-mediated cellular immunity have been remarkably ineffective, probably owing to our limited understanding of the mechanisms for establishing and maintaining T cell effector function and memory. This proposal investigates how two T- box family transcription factors contribute to the formation of cellular immunity. Eomesodermin and T-bet redundantly ensure CD8+ T cells become cytotoxic effector cells but they also seem to oppose each other's functions in normal and abnormal CD8+ T cell differentiation. This allows the two transcription factors to form an adjustable balance between the opposing demands of terminal differentiation and self-renewal. The specific aims of this project will address how and when Eomes functions in memory T cell programming. The aims will also resolve whether the predominant actions of Eomes in memory cells are on a unique set of genes or whether Eomes is controlling CD8+ T cell memory through interplay with T-bet at loci they regulate in common. Successful execution of the 3 specific aims of this proposal should provide new insight into the mechanisms of gene induction and cellular differentiation in the immune response. It is also anticipated that these studies will yield new strategies for defending us against a variety of infectious diseases that are the focus of our CD8+ T cell responses.