Regulation of Innate Dendritic Cell CTLA-4

摘要 利用细胞介导的（TH 1）免疫来治疗癌症或建立预防性免疫的前景 对艾滋病毒等慢性病毒病原体的不完全了解继续阻碍着许多 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， 用于平衡、调节和微调免疫激活与稳态抑制的分子。的 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 不受控制的淋巴增生和自身免疫性炎症CTLA-4由所有主要淋巴细胞表达。 包括T、B和NK细胞在内的谱系效应子;然而，其功能性在T细胞中得到了最好的表征 其中它表现出细胞外在和细胞内在的调节功能。几乎没有人知道 CTLA-4在非淋巴样细胞类型中的表达或功能，以及非淋巴样细胞中CTLA-4表达的零星报道。 淋巴谱系一直没有定论。最近，我们的小组报道了表达和分泌 来自骨髓谱系先天树突细胞（DC）的微泡结合的CTLA-4。微泡CTLA-4 示威者 艾德结合B7的能力，导致囊泡内化和随后的B7表达下调。 DC表达的CTLA-4的敲低导致CD 8+细胞增殖的显著上调， 增强体内抗肿瘤和抗病毒免疫。非淋巴CTLA-4表达的发现， 先天细胞类型和随之而来的新功能特征标志着细胞生物学的重大范式转变 了解CTLA-4在免疫治理中的作用以及先天性和适应性免疫的方式 免疫系统的手臂进行交流。成功完成此处建议的工作， DC表达CTLA-4的基本调节机制以及这种关键调节的方式， 免疫调节分子有助于先天免疫和适应性免疫之间串扰。这些数据将 促进和加速开发新的治疗方法，并协助加强利用 靶向CTLA-4检查点通路的现有治疗剂（即伊匹单抗）。

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.