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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：
10267698
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/10267698
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.

项目总结