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.

项目摘要 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 它们的克隆性扩增和分化为特化的终末效应细胞群或长期存活 存储单元。虽然产生效应器和记忆性CD8+T细胞是清除 细胞内感染，并形成针对广泛病原体和 抗癌免疫治疗中，CD8+T细胞也可引起自身免疫组织损伤，并对 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 不同群体的效应性和记忆性CD8+T细胞的动态平衡仍不完全。我们有 发现CD8+T细胞激活后，信号转接子BCAP迅速上调 细胞。此外，我们还发现，BCAP的缺失会损害CD8+T细胞的正常克隆性增殖，并改变 效应/记忆细胞分化。因此，我们将BCAP确定为关键的和以前的 帮助控制CD8+T细胞激活结果的未知信号中枢。因此，更好地 了解BCAP的功能并确定其相关的信号通路将有助于定义分子 为CD8+T细胞功能奠定基础，为CD8+T细胞的治疗调控提供新靶点 回应。在这项建议中，我们将在这些令人振奋的初步研究的基础上，全面确定 BCAP依赖的信号转导如何影响效应器和记忆的增殖、分化和功能 CD8+T细胞，并确定由BCAP调控的关键分子通路，帮助控制每一个 流程。