Control of CD8+ effector T cell Differentiation

描述（由申请人提供）：细胞介导的免疫对于宿主防御所有类型的病原体和发生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非常无效，可能是由于我们对建立和维持T细胞效应功能和记忆的机制了解有限。本研究旨在探讨促进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细胞的分子特征都是由T-box基因家族的一组同源转录因子Eomesodermin和T-bet调控的。在CD4+和CD8+ T细胞中，这两种转录因子的冗余、协同或排他性作用可能是诱导细胞免疫和记忆的必要条件。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中的作用。将进行研究，以确定Eomesodermin和T-bet在体外模拟分化诱导效应T细胞谱系限制特征中的精确贡献。利用感染性疾病的体内模型，包括单核增生李斯特菌和淋巴细胞性脉络膜脑膜炎病毒的攻击，将用来表征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功能、持久免疫和记忆T细胞生成方面发挥因果作用。这3个目标的成功实施将为免疫应答中的基因诱导和细胞分化机制提供新的见解。我们还预计，这些研究将产生新的策略来保护我们免受各种传染病的侵害，这些传染病是我们CD8+ T细胞反应的重点。

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.