PD-L1 reverse signaling in dermal DCs promotes DC migration and skin immunity to cutaneous pathogens

真皮 DC 中的 PD-L1 反向信号传导促进 DC 迁移和皮肤对皮肤病原体的免疫

基本信息

批准号：
10093965
负责人：
Beth Ann Tamburini
金额：
$ 45.24万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10093965
关键词：
Actins Address Alanine Amino Acid Motifs Amino Acids Antigens Apoptosis Archives Autoimmune Process CCL21 gene CD80 gene Cells Cutaneous Cytolysis Cytoplasmic Tail Cytotoxic T-Lymphocytes Data Defect Dendritic Cells Dermal Development Event Extracellular Domain Goals Human IRF1 gene Immune Immune response Immunity Immunization In Vitro Infection Inflammatory Response Interferons Listeriosis Lymphatic Lymphatic Capillaries Malignant Neoplasms Memory Molecular Mus Mutate Mutation Publishing Regulation Role Signal Transduction Skin Stimulus Systemic infection T cell response T memory cell T-Cell Proliferation T-Lymphocyte Therapeutic Intervention Time Tissues Vaccination Vaccinia Virus Diseases XCR1 gene adaptive immunity anti-PD-L1 base cancer cell cell motility cell type chemokine draining lymph node experience extracellular improved in vivo lymph nodes migration mouse model novel pathogen polymerization programmed cell death ligand 1 programmed cell death protein 1 response trafficking transcription factor tumor progression

项目摘要

Project Summary The goal of this proposal is to identify the mechanism(s) by which PD-L1 reverse signaling in dendritic cells (DC) initiates DC trafficking, T cell priming and T cell programming during cutaneous infection. Our studies have outlined a major role for PD-L1 reverse signaling in the control of DC migration from the skin to the draining lymph node. Intriguingly, this loss of migration appears to be dependent on TLR stimulation or infections that initiate type 1 IFN signaling. These findings are consistent with PD-L1 acting to mitigate type 1 IFN signaling events. We also outline a requirement for PD-L1 reverse signaling in chemokine, but not S1P, responsiveness demonstrating a new role for PD-L1 in regulating chemokine signaling. Finally, we find T cell priming in the lymph node is significantly decreased in the absence of PD-L1 reverse signaling. However, these defects in T cell priming only occur when DC trafficking is required, and not when antigens drain directly through the lymphatics and to the LN nor following systemic infection. Therefore, in this proposal we aim to better understand the requirements for PD-L1 reverse signaling in dendritic cell transmigration through the lymphatic capillaries. We also aim to understand how the extracellular and intracellular domains of PD-L1 may control responsiveness to chemokines. Finally, we aim to address the contribution of DC retention in the skin caused by loss of PD-L1 signaling to tissue resident memory responses established after vaccinia scarification.

项目摘要该建议的目的是确定树突状细胞中PD-L1反向信号的机制（DC）在皮肤感染过程中启动直流运输，T细胞启动和T细胞编程。我们的研究概述了PD-L1反向信号传导的主要作用排水淋巴结。有趣的是，这种迁移的丧失似乎取决于TLR刺激或启动1型IFN信号的感染。这些发现与PD-L1作用以减轻1型1一致 IFN信号事件。我们还概述了趋化因子中PD-L1反向信号传导的要求，而不是S1P的要求响应能力表明PD-L1在调节趋化因子信号传导中发挥了新作用。最后，我们发现T细胞在没有PD-L1反向信号传导的情况下，淋巴结中的启动显着降低。然而，这些缺陷在T细胞启动中只有在需要DC运输时才发生，而不是当抗原直接排出通过淋巴管和LN或遵循全身感染。因此，在此提案中，我们的目标是更好地了解树突状细胞中PD-L1反向信号传导的要求淋巴毛细血管。我们还旨在了解PD-L1的细胞外和细胞内结构域如何控制趋化因子的反应能力。最后，我们旨在解决DC保留在皮肤中的贡献由PD-L1信号传导损失对疫苗疤痕后建立的组织驻留记忆反应引起的。