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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：
10461928
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/10461928
关键词：
Actins Address Alanine Amino Acid Motifs Amino Acids Antigens Apoptosis Archives Autoimmune 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 Infectious Skin Diseases 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.

项目概要该提案的目标是确定树突状细胞中 PD-L1 逆转信号传导的机制 (DC) 在皮肤感染期间启动 DC 运输、T 细胞启动和 T 细胞编程。我们的研究概述了 PD-L1 反向信号在控制 DC 从皮肤迁移到皮肤的过程中的主要作用引流淋巴结。有趣的是，这种迁移的丧失似乎依赖于 TLR 刺激或启动 1 型 IFN 信号传导的感染。这些发现与 PD-L1 缓解 1 型疾病的作用一致干扰素信号传导事件。我们还概述了趋化因子中 PD-L1 反向信号传导的要求，但 S1P 除外，反应性证明了 PD-L1 在调节趋化因子信号传导中的新作用。最后，我们找到了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减少。然而， T 细胞启动中的这些缺陷仅在需要 DC 运输时发生，而不是在抗原直接排出时发生通过淋巴管到达淋巴结，也不会在全身感染后发生。因此，在本提案中，我们的目标是通过以下方法更好地了解树突状细胞迁移中 PD-L1 反向信号传导的要求毛细淋巴管。我们还旨在了解 PD-L1 的胞外和胞内结构域如何发挥作用控制对趋化因子的反应。最后，我们的目标是解决皮肤中 DC 保留的贡献这是由于痘苗划痕后建立的组织驻留记忆反应的 PD-L1 信号丧失所致。