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) 是先天免疫的重要谱系，是主要的接触点和 CTLA-4 的先天性和适应性免疫系统之间的串扰是最具有特征的之一。 免疫检查点蛋白、用于平衡、调节和微调免疫激活的分子 CTLA-4 由所有主要淋巴谱系效应子表达；然而，其功能 - T 细胞的特性得到了最好的表征，它表现出细胞外在和细胞内在的调节功能。 直到最近，人们对 CTLA-4 在非淋巴细胞类型中的表达或功能知之甚少。 特别是骨髓谱系树突状细胞亚群，在此更新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+ 外泌体可以旁分泌方式结合 B7，从而导致 囊泡内化以及随后内化的旁观者 DC 中 B7 表达的下调 CTLA-4+外泌体脱机后，DC表达的CTLA-4的敲低导致了显着的上调。 体外共培养的 CD8+ 细胞增殖以及体内抗肿瘤和抗病毒免疫力的增强。 骨髓 CTLA-4 表达的发现和伴随特征标志着医学领域的范式转变 了解 CTLA-4 在免疫治理中的作用以及先天和免疫调节的机制 随后的数据表明 DC CTLA-4 的表达受到调节。 TH 极化线索，DC 的调节似乎部分受转录因子 GATA3 控制 C/EBP-b 此外，C57BL/6 背景中 CTLA-4 的条件消融揭示了潜在的新作用。 DC 在胸腺和其他淋巴组织（包括派耶氏淋巴组织）的调节过程中表达 CTLA-4 这些新颖且令人兴奋的数据使得我们能够提出一个完善的总体假设，即 DC- 分泌的 CTLA-4+ 外泌体充当效应载体，塑造适应性重组的下游 TH 极化 我们将通过三个独立的目标来测试先天信号线索的 DC 检测所指示的响应。 这一总体假设通过 i) 定义 TH 极化线索在 DC CTLA-4 治理中的作用表达了- CEBP/b 和 GATA3 转录调节因子的作用和治理，ii) 定义机制 DC 分泌的 CTLA-4+ 和 CTLA-4neg 外泌体通过其调节下游适应性 TH 极化， iii) 通过询问 DC CTLA-4 表达调节中枢耐受性的方式 在 CD11c-Cre CTLA-4flox/flox C57BL/6 小鼠中观察到的调节性 T 细胞缺陷 完成这些指标。 悬而未决的目标将进一步阐明骨髓 CTLA-4 的新调节作用，进一步提高合成能力 有效和强大的疫苗接种策略，同时表征关键的可药物靶标相互作用并确保 提高对复杂生物途径的理解。

项目成果

Genetic Adjuvantation of a Cell-Based Therapeutic Vaccine for Amelioration of Chagasic Cardiomyopathy.

用于改善恰加斯心肌病的细胞治疗疫苗的遗传佐剂。

• 发表时间: 2017
• 影响因子: 3.1
• 作者: Konduri, Vanaja;Halpert, Matthew M;Liang, Dan;Levitt, Jonathan M;Cruz;Zhan, Bin;Bottazzi, Maria Elena;Hotez, Peter J;Jones, Kathryn M;Decker, William K
• 通讯作者: Decker, William K

Dendritic cell vaccination plus low-dose doxorubicin for the treatment of spontaneous canine hemangiosarcoma.

树突状细胞疫苗接种加低剂量阿霉素治​​疗自发性犬血管肉瘤。

• 发表时间: 2019
• 影响因子: 6.4
• 作者: Konduri, V;Halpert, M M;Baig, Y C;Coronado, R;Rodgers, J R;Levitt, J M;Cerroni, B;Piscoya, S;Wilson, N;DiBernardi, L;Omarbekov, Z;Seelhoff, L;Ravi, V;Douglass, L;Decker, W K
• 通讯作者: Decker, W K

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

超越 T 细胞：免疫和非免疫细胞类型中 CTLA-4 表达的功能表征。

• 发表时间: 2020
• 作者: Oyewole;Konduri, Vanaja;Vazquez;Weldon, Scott A;Levitt, Jonathan M;Decker, William K
• 通讯作者: Decker, William K

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

癌症免疫疗法：临床革命和新兴临床前动物模型的历史视角。

• 发表时间: 2017
• 作者: Decker, William K;da Silva, Rodrigo F;Sanabria, Mayra H;Angelo, Laura S;Guimarães, Fernando;Burt, Bryan M;Kheradmand, Farrah;Paust, Silke
• 通讯作者: Paust, Silke

CD8+CD161+ T-Cells: Cytotoxic Memory Cells With High Therapeutic Potential.

CD8 CD161 T 细胞：具有高治疗潜力的细胞毒性记忆细胞。

• 发表时间: 2020
• 作者: Konduri, Vanaja;Oyewole;Vazquez;Weldon, Scott A;Halpert, Matthew M;Levitt, Jonathan M;Decker, William K
• 通讯作者: Decker, William K