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经历癌性转化的细胞至关重要。接种疫苗或增强T淋巴细胞介导的细胞免疫的策略已经非常无效，可能是由于我们对建立和维持T细胞效应功能和记忆的机制的理解有限。该建议调查有助于形成细胞免疫的转录机制。初步的证据支持的模型，CD 8+效应和记忆T细胞的分子特征的调节由一个旁系同源的一组转录因子从T-盒家族的基因，Eomesodermin和T-bet。这两种转录因子的冗余、协同或排他性作用可能对诱导CD 4+和CD 8 + T细胞的细胞免疫和记忆至关重要。该提案旨在进一步确定Eomesodermin在体外和体内CD 8 + T细胞效应器和记忆分化过程中的作用。将进行研究以使用体外模拟分化来确定Eomesodermin和T-bet在诱导效应T细胞的谱系限制特征中的精确贡献。使用体内感染性疾病模型，包括单核细胞增生李斯特菌和淋巴细胞性脉络丛脑膜炎病毒的挑战，将用于表征Eomesodermin和T-bet表达的动态模式，并确定这2个因子是否在促进效应子功能，持久免疫和记忆T细胞生成中发挥因果作用。这一建议的3个具体目标的成功执行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。预计这些研究将产生新的策略，以保护我们免受各种传染病的侵害，这些传染病是我们CD 8 + 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.