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。这项建议研究了有助于细胞免疫形成的转录机制。初步证据支持一个模型，即CD8+效应T细胞和记忆T细胞的分子特征都受T-box家族基因Eomesodermin和T-bet中一组相似的转录因子的调控。这两个转录因子的冗余、协同或排他性作用可能是诱导CD4+和CD8+T细胞的细胞免疫和记忆所必需的。本研究旨在进一步明确Eomesodermin在体内和体外CD8+T细胞效应和记忆分化过程中的作用。将进行研究，以确定Eomesodermin和T-bet在通过体外模拟分化诱导效应性T细胞的谱系限制性特征方面的确切贡献。使用感染疾病的体内模型，包括单核细胞增多性李斯特菌和淋巴细胞性脉络膜脑膜炎病毒的挑战，将被用来表征Eomesodermin和T-bet的动态表达模式，并确定这两个因素是否在促进效应器功能、持久免疫和记忆T细胞生成方面发挥因果作用。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 the transcriptional mechanisms contributing to the formation of cellular immunity. Preliminary evidence is offered in support of a model that the molecular signatures of both CD8+ effector and memory T cells are regulated by a paralogous set of transcription factors from the T-box family of genes, Eomesodermin and T-bet. Either the redundant, concerted, or exclusive action of these two transcription factors may be essential for induction of cellular immunity and memory in both CD4+ and CD8+ T cells. This proposal aims to further define the role of Eomesodermin during CD8+ T cell effector and memory differentiation, in vitro and in vivo. Studies will be undertaken to define the precise contribution of Eomesodermin and T-bet in inducing lineage-restricted characteristics of effector T cells using modeled differentiation in vitro. Use of in vivo models of infectious diseases, including challenges with Listeria monocytogenes and Lymphocytic Choriomeningitis Virus, will be used to characterize the dynamic patterns of expression of Eomesodermin and T-bet, and determine whether these 2 factors play a causal role in promoting effector function, durable immunity, and memory T cell generation. Successful execution of the 3 specific aims of this proposal should provide new insight into the mechanisms of gene induction and cellular differentiation in 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.