Regulation of Innate Dendritic Cell CTLA-4

先天树突状细胞 CTLA-4 的调节

• 批准号: 9882949
• 负责人: WILLIAM Karl DECKER
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-13 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9882949
• 关键词: Adaptive Immune System; Animals; Autoimmune Process; B-Lymphocytes; Binding; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Patient; Cell Proliferation; Cells; Chronic; Data; Dendritic Cells; Development; Down-Regulation; Elderly; Elements; Equilibrium; Exhibits; General Population; HIV; Immune; Immune system; Immunity; Individual; Inflammation; Lymphoid; Malignant Neoplasms; Mediating; Myelogenous; Natural Immunity; Natural Killer Cells; Pathway interactions; Phenotype; Process; Production; Proteins; Regulation; Reporting; Risk; Role; T cell regulation; T-Cell Activation; T-Lymphocyte; Therapeutic; Tumor Immunity; Up-Regulation; Vaccines; Vesicle; Viral Vaccines; Work; adaptive immunity; antiviral immunity; arm; base; cell type; chronic infection; immune activation; immune checkpoint; immunoregulation; in vivo; knock-down; microvesicles; mutant; neonate; novel; novel therapeutic intervention; pathogenic virus; postnatal period; prophylactic

Abstract The promise of harnessing cell-mediated (TH1) immunity to treat cancer or establish prophylactic immunity against chronic viral pathogens like HIV continues to be hampered by an incomplete understanding of many different critical factors and processes, including the manner by which the innate and adaptive immune systems interface and communicate. CTLA-4 is one of the best characterized of the immune checkpoint proteins, molecules that serve to balance, regulate, and fine-tune immune activation with homeostatic inhibition. The critical importance of CTLA-4 to the regulation of T-cell activation and proliferation was demonstrated nearly two decades ago by the dramatic phenotype of the null mutant, animals which die in the early postnatal period of uncontrolled lymphoproliferation and autoimmune inflammation. CTLA-4 is expressed by all major lymphoid lineage effectors including T, B, and NK cells; however, its functionality has been best characterized in T-cells where it exhibits both cell-extrinsic and cell-intrinsic regulatory functions. There is almost nothing known about CTLA-4 expression or function in non-lymphoid cell types, and sporadic reports of CTLA-4 expression in non- lymphoid lineages have been inconclusive. Recently our group reported expression and secretion of microvesicle-bound CTLA-4 from myeloid lineage innate dendritic cells (DC). Microvesicular CTLA-4 demonstrat ed the ability to bind B7, leading to vesicle internalization and subsequent downregulation of B7 expression. Knockdown of DC-expressed CTLA-4 resulted in a dramatic upregulation of CD8+ cell proliferation as well as enhanced antitumor and antiviral immunity in vivo. The discovery of non-lymphoid CTLA-4 expression in an innate cell type and concomitant characterization of novel function signifies a significant paradigm shift in the understanding of CTLA-4's role in immune governance as well as the manner by which the innate and adaptive arms of the immune system communicate. Successful completion of the work proposed herein will characterize the basic mechanisms by which DC expressed CTLA-4 is regulated as well as the manner by which this critical immunoregulatory molecule contributes to crosstalk between innate and adaptive immunity. These data will enable and accelerate development of novel therapeutic approaches and assist in enhanced exploitation of existing therapeutics (i.e. ipilimumab) that target CTLA-4 checkpoint pathways.

抽象的 利用细胞介导的 (TH1) 免疫来治疗癌症或建立预防性免疫的前景 由于对许多因素的不完全了解，针对艾滋病毒等慢性病毒病原体的研究仍然受到阻碍 不同的关键因素和过程，包括先天性和适应性免疫的方式 系统接口和通信。 CTLA-4 是最具特征的免疫检查点蛋白之一， 通过稳态抑制来平衡、调节和微调免疫激活的分子。这 CTLA-4 对 T 细胞活化和增殖的调节至关重要 二十年前，由于无效突变体的戏剧性表型，动物在产后早期死亡 不受控制的淋巴细胞增殖和自身免疫性炎症。 CTLA-4 由所有主要淋巴组织表达 谱系效应细胞，包括 T、B 和 NK 细胞；然而，其功能在 T 细胞中得到了最好的表征 它表现出细胞外在和细胞内在的调节功能。对此几乎一无所知 CTLA-4 在非淋巴细胞类型中的表达或功能，以及 CTLA-4 在非淋巴细胞中表达的零星报告 淋巴谱系尚无定论。最近我们课题组报道了 来自骨髓谱系先天树突状细胞 (DC) 的微泡结合 CTLA-4。微泡CTLA-4 展示 ed 结合 B7 的能力，导致囊泡内化和随后 B7 表达的下调。 DC 表达的 CTLA-4 的敲低导致 CD8+ 细胞增殖以及 增强体内抗肿瘤和抗病毒免疫力。发现非淋巴细胞 CTLA-4 表达 先天细胞类型和新功能的伴随特征标志着细胞学领域的重大范式转变 了解 CTLA-4 在免疫治理中的作用以及先天性和适应性的免疫调节方式 免疫系统的手臂进行交流。成功完成本文提出的工作将具有以下特点： DC表达CTLA-4的基本机制以及这一关键的调节方式 免疫调节分子有助于先天免疫和适应性免疫之间的串扰。这些数据将 促进并加速新型治疗方法的开发，并协助加强对药物的利用 针对 CTLA-4 检查点通路的现有疗法（即 ipilimumab）。