Control of CD8+ T cell activation and differentiation by the signaling adaptor BCAP

信号适配器 BCAP 控制 CD8 T 细胞活化和分化

• 批准号: 9177685
• 负责人: Daniel J Campbell
• 金额: $ 53.13万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-08 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177685
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Address; Autoimmune Process; Autoimmunity; B-Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell physiology; Cells; Cellular Immunity; Clinical; Clonal Expansion; Communicable Diseases; Development; Effector Cell; Event; Generations; Goals; Guanine Nucleotide Exchange Factors; Homeostasis; Human; Immune System Diseases; Infection; Insulin-Dependent Diabetes Mellitus; Knowledge; Life; Memory; Molecular; Mus; Outcome; Pathway interactions; Population; Process; Regulation; Sampling; Signal Pathway; Signal Transduction; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Tissue Transplantation; Tissues; Transplantation; Vaccination; Virus Diseases; base; cancer immunotherapy; cytokine; in vivo; innovation; insight; mouse model; neoplasm immunotherapy; novel; pathogen; research study; response; vaccination strategy

Project Summary CD8+ T cells integrate signals from the T cell receptor, co-stimulatory molecules, and cytokines that control their clonal expansion and differentiation into specialized populations of terminal effector cells or long-lived memory cells. Although the generation of effector and memory CD8+ T cells is required for clearance of intracellular infections and forms the basis for vaccination strategies against a wide-range of pathogens and anti-cancer immunotherapy, CD8+ T cells can also cause autoimmune tissue damage, and are a barrier to effective tissue transplantation. Thus, understanding the molecular control of CD8+ T cell expansion, differentiation and function will have wide-ranging applications in manipulating CD8+ T cell responses in the contexts of vaccination and infectious disease, autoimmunity, transplantation and tumor immunotherapy. However, despite extensive study our knowledge of the key molecules that direct the differentiation, function and homeostasis of different populations of effector and memory CD8+ T cells remains incomplete. We have made the novel observation that the signaling adaptor BCAP is rapidly upregulated upon activation of CD8+ T cells. Moreover, we show that loss of BCAP impairs normal clonal expansion of CD8+ T cells and alters effector/memory cell differentiation. Thus, we have identified BCAP as a critical and previously uncharacterized signaling hub that helps control the outcome of CD8+ T cell activation. Thus, better understanding BCAP function and identifying its associated signaling pathways will help define the molecular basis for CD8+ T cell function, and provide new targets for therapeutically manipulating of CD8+ T cell responses. In this proposal, we will build on these exciting preliminary studies to comprehensively determine how BCAP-dependent signaling impacts the proliferation, differentiation and function of effector and memory CD8+ T cells, and to define the key molecular pathways regulated by BCAP that help control each of these processes.

项目概要 CD8+ T 细胞整合来自 T 细胞受体、共刺激分子和控制细胞因子的信号 它们的克隆扩增和分化为特殊的终末效应细胞群或长寿命细胞 记忆细胞。尽管效应和记忆 CD8+ T 细胞的产生是清除 细胞内感染，并构成针对多种病原体的疫苗接种策略的基础 抗癌免疫治疗中，CD8+ T细胞也会引起自身免疫组织损伤，是免疫治疗的屏障 有效的组织移植。因此，了解 CD8+ T 细胞扩增的分子控制， 分化和功能将在操纵 CD8+ T 细胞反应方面具有广泛的应用 疫苗接种和传染病、自身免疫、移植和肿瘤免疫治疗的背景。 然而，尽管我们对指导分化、功能的关键分子进行了广泛的研究， 不同效应和记忆 CD8+ T 细胞群体的稳态仍然不完整。我们有 进行了新的观察，即信号适配器 BCAP 在 CD8+ T 激活后迅速上调 细胞。此外，我们发现 BCAP 的缺失会损害 CD8+ T 细胞的正常克隆扩增，并改变 效应细胞/记忆细胞分化。因此，我们已将 BCAP 确定为关键且先前的 未表征的信号中枢，有助于控制 CD8+ T 细胞激活的结果。这样，更好 了解 BCAP 功能并识别其相关信号通路将有助于定义分子 为 CD8+ T 细胞功能奠定基础，并为 CD8+ T 细胞的治疗操作提供新靶点 回应。在本提案中，我们将在这些令人兴奋的初步研究的基础上全面确定 BCAP 依赖性信号传导如何影响效应器和记忆的增殖、分化和功能 CD8+ T 细胞，并定义 BCAP 调节的关键分子途径，帮助控制这些途径 流程。