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）免疫治疗癌症或建立预防性免疫的承诺 反对像艾滋病毒这样的慢性病毒病原体，对许多人的不完全理解继续阻碍 不同的关键因素和过程，包括先天和适应性免疫的方式 系统接口和通信。 CTLA-4是免疫检查点蛋白的最佳特征之一， 用于平衡，调节和微调免疫激活与稳态抑制的分子。这 CTLA-4对调节T细胞激活和增殖的至关重要的重要性几乎证明 二十年前，由于无效突变体的戏剧表型，在产后早期死亡的动物 不受控制的淋巴细胞增生和自身免疫性炎症。 CTLA-4由所有主要淋巴表达 谱系效应子，包括T，B和NK细胞；但是，它的功能在T细胞中的表征最佳 它表现出细胞 - 超支和细胞中性调节功能。几乎一无所知 非淋巴细胞类型中的CTLA-4表达或功能，以及非淋巴样细胞类型的偶发报告 淋巴谱系尚无定论。最近，我们的小组报告了表达和分泌 来自髓样谱系的固有树突状细胞（DC）的微囊泡结合的CTLA-4。 Microvescular CTLA-4 演示 ED结合B7的能力，导致囊泡内在化和随后的B7表达下调。 DC表达的CTLA-4的敲低导致CD8+细胞增殖的显着上调 体内增强的抗肿瘤和抗病毒免疫。发现非淋巴CTLA-4表达 新颖功能的先天细胞类型和伴随的表征表示明显的范式转移 了解CTLA-4在免疫治理中的作用以及先天和适应性的方式 免疫系统的臂进行通信。成功完成本文提出的工作将表征 DC表达CTLA-4的基本机制以及这种关键的方式。 免疫调节分子有助于先天和适应性免疫之间的串扰。这些数据将 实现并加速新的治疗方法的发展，并有助于增强对 靶向CTLA-4检查点途径的现有治疗剂（即ipilimumab）。