Regulation of Innate Dendritic Cell CTLA-4

先天树突状细胞 CTLA-4 的调节

• 批准号: 10747694
• 负责人: WILLIAM Karl DECKER
• 金额: $ 47.88万
• 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 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747694
• 关键词: ATAC-seq; Ablation; Adoptive Transfer; Age; Alopecia; Animals; Antigens; Autoimmune Diseases; B-Lymphocytes; Binding; Biological; C57BL/6 Mouse; CCAAT-Enhancer-Binding Proteins; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cell Communication; Cell Proliferation; Cell Separation; Cell secretion; Cells; Cellular Immunity; Cellular biology; Cessation of life; ChIP-seq; Coculture Techniques; Communicable Diseases; Complex; Cues; Data; Dendritic Cells; Detection; Disease; Down-Regulation; Equilibrium; Event; Exhibits; Failure to Thrive; Formulation; Funding; GATA3 gene; Genetic Transcription; Genomics; Health; Human; ITGAX gene; Immune; Immune response; Immune system; In Vitro; Incubated; Infectious Agent; Interferon Type II; Intervention; Knock-out; LoxP-flanked allele; Lymphocytic Infiltrate; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Pancreas; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Peyer' s Patches; Pharmacologic Substance; Phenotype; Play; Population; Process; Proliferating; Proteins; Publishing; Regulation; Regulatory T-Lymphocyte; Resolution; Role; Shapes; Signal Transduction; Small Interfering RNA; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transcriptional Regulation; Treatment Protocols; Tumor Immunity; Up-Regulation; Vesicle; Virus Diseases; Work; antiviral immunity; arm; cell type; central tolerance; conditional knockout; druggable target; exosome; fluorescence imaging; immune activation; immune checkpoint; immune function; immunoregulation; in vivo; knock-down; knockout animal; lymphoid organ; monocyte; novel; novel vaccines; paracrine; polarized cell; programs; promoter; response; therapeutic target; thymocyte; transcriptome sequencing; transmission process; vaccination strategy

Abstract Myeloid dendritic cells (DC) are a critical lineage of innate immunity that serve as a principal point of contact and crosstalk between the innate and adaptive arms of the immune system. 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. CTLA-4 is expressed by all major lymphoid lineage effectors; however, its function- ality has been best characterized in T-cells where it exhibits both cell-extrinsic and cell-intrinsic regulatory func- tions. Until recently, very little was known about CTLA-4 expression or function in non-lymphoid cell types, par- ticularly the myeloid lineage dendritic cell subsets. In the original iteration of this renewal application, we provided preliminary data demonstrating that DC-secreted CTLA-4+ exosomes could bind B7 in paracrine fashion, leading to vesicle internalization and subsequent downregulation of B7 expression among bystander DC that internalized the CTLA-4+ exosomes. Conversely, knockdown of DC-expressed CTLA-4 resulted in a dramatic upregulation of co-cultured CD8+ cell proliferation in vitro as well as enhanced antitumor and antiviral immunity in vivo. These discoveries and concomitant characterization of myeloid CTLA-4 expression signified a paradigm shift in the understanding of CTLA-4’s role in immune governance as well as the mechanisms through which innate and adaptive crosstalk occur. Subsequent data indicated that the expression of DC CTLA-4 is modulated in response to TH polarizing cues and that regulation in DC appears to be governed in part by the transcription factors GATA3 and C/EBP-b. Further, conditional ablation of CTLA-4 in the C57BL/6 background revealed potential new roles for DC expressed CTLA-4 in regulatory processes in the thymus and in other lymphoid tissues including Peyer’s patches. These novel and exciting data have allowed formulation of a refined overarching hypothesis that DC- secreted CTLA-4+ exosomes act as effector vehicles that shape downstream TH polarization of adaptive re- sponses as dictated by DC detection of innate signaling cues. By means of three independent aims we will test this overarching hypothesis by i) defining the role of TH polarizing cues in the governance of DC CTLA-4 expres- sion and the governance of the CEBP/b and GATA3 transcriptional regulators, ii) defining the mechanisms through which DC-secreted CTLA-4+ and CTLA-4neg exosomes regulate downstream adaptive TH polarization, and iii) defining the manner by which DC CTLA-4 expression modulates central tolerance by interrogating the regulatory T-cell deficits observed in the CD11c-Cre CTLA-4flox/flox C57BL/6 mouse. Completion of these inde- pendent aims will further elucidate the novel regulatory role of myeloid CTLA-4, furthering the ability to synthesize effective and powerful vaccination strategies while characterizing critical druggable target interactions and en- hancing the understanding of complex biological pathways.

抽象的 髓样树突状细胞（DC）是先天免疫的关键谱系，作为主要接触点， 免疫系统先天和适应性臂之间的串扰。 CTLA-4是最佳特征之一 在免疫粘点蛋白中，用于平衡，调节和微调免疫激活的分子 具有稳态抑制。 CTLA-4由所有主要的淋巴谱系效应表达。但是，其功能 - 在T细胞中，Ality的表征最佳，在T细胞中表现出细胞 - 超支和细胞中的调节性功能 tions。直到最近，关于非淋巴样细胞类型中的CTLA-4表达或功能知之甚少 寺庙髓样谱系树突状细胞子集。在此续订应用程序的原始迭代中，我们提供了 初步数据表明，DC分泌的CTLA-4+外泌体可以以旁分线结合B7，领先 在内部化的旁观者DC中，场地内部化和随后的B7表达下调 CTLA-4+外泌体。相反，DC表达的CTLA-4的敲低导致了戏剧性的上调 体外共培养的CD8+细胞增殖以及体内增强的抗肿瘤和抗病毒免疫。这些 髓样CTLA-4表达的发现和伴随的表征签署了范式的转变 了解CTLA-4在免疫跨性别中的作用以及先天和先天性的机制 自适应串扰发生。随后的数据表明，DC CTLA-4的表达被调制为响应 对于TH极化线索和DC中的调节似乎部分由转录因子GATA3控制 和C/EBP-B。此外，C57BL/6背景中CTLA-4的条件消融揭示了潜在的新角色 DC在胸腺和其他淋巴组织中的调节过程中表达的CTLA-4（包括Peyer的） 补丁。这些新颖而令人兴奋的数据允许了DC-的精致总体假设的公式 分泌的CTLA-4+外泌体充当效应器车辆，在下游自适应重新极化 DC检测先天信号提示所指示的赞助。通过三个独立目标，我们将测试 通过i）定义了第三个偏振线索在DC CTLA-4 Express-治理中的作用的总体假设 CEBP/B和GATA3转录调节器的sion和治理，ii）定义机制 DC分泌的CTLA-4+和CTLA-4NEG外泌体调节下游自适应TH极化， iii）定义DC CTLA-4表达通过询问调节中心容忍的方式 调节性T细胞定义在CD11C-CRE CTLA-4FLOX/FLOX C57BL/6小鼠中观察到的。完成这些 吊坠目标将进一步阐明髓样CTLA-4的新调节作用，从而增强合成的能力 有效而有力的疫苗接种策略，同时表征了关键的可药物靶点相互作用和 对复杂的生物途径的理解有所了解。

项目成果

Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models.

• DOI: 10.3389/fimmu.2017.00829
• 发表时间: 2017
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Decker WK;da Silva RF;Sanabria MH;Angelo LS;Guimarães F;Burt BM;Kheradmand F;Paust S
• 通讯作者: Paust S

Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types.

• DOI: 10.3389/fimmu.2020.608024
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Oyewole-Said D;Konduri V;Vazquez-Perez J;Weldon SA;Levitt JM;Decker WK
• 通讯作者: Decker WK