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细胞整合了来自T细胞受体，共刺激分子和控制细胞因子的信号 它们的克隆膨胀和分化为末端效应细胞的专业人群或长寿 记忆单元。尽管效应子和内存CD8+ T细胞的产生需要清除 细胞内感染并构成了针对广泛病原体的疫苗接种策略的基础 抗癌免疫疗法，CD8+ T细胞也可能引起自身免疫组织损伤，并且是 有效的组织移植。因此，了解CD8+ T细胞膨胀的分子控制， 分化和功能将在操纵CD8+ T细胞响应中具有广泛的应用 疫苗接种和传染病，自身免疫，移植和肿瘤免疫疗法的情况。 但是，尽管进行了广泛研究，但我们对指导分化的关键分子的了解，功能 效应子和记忆CD8+ T细胞的不同种群的稳态仍然不完整。我们有 使新的观察结果是，在激活CD8+ T时，信号适配器BCAP迅速上调 细胞。此外，我们表明，BCAP的损失会损害CD8+ T细胞的正常克隆膨胀并改变 效应子/记忆细胞分化。因此，我们将BCAP确定为关键和以前 有助于控制CD8+ T细胞激活结果的未表征信号枢纽。因此，更好 了解BCAP功能并识别其相关的信号通路将有助于定义分子 CD8+ T细胞功能的基础，并为操纵CD8+ T细胞提供了新的目标 回答。在此提案中，我们将基于这些令人兴奋的初步研究，以全面确定 BCAP依赖性信号如何影响效应子和记忆的增殖，分化和功能 CD8+ T细胞，并定义由BCAP调节的关键分子途径，该途径有助于控制这些途径 过程。