Irradiation-Induced CD62L Shedding in Human Plasmacytoid Dendritic Cells Depends on ADAM17 and p38 MAPK

Plasmacytoid dendritic cells (PDCs) represent a crucial bridge between innate and adaptive immunity as they can recognise viruses and viral-infected cells, secrete type I interferon and prime naive T-cell responses. Like naive T cells, PDCs express CD62L, an essential molecule involved in the trans-endothelial migration process, and are supposed to travel directly from blood to lymph nodes to prime naive T cells. We developed a therapeutic PDC line model (PDC*line) derived from a patient with blastic PDC neoplasm, and showing high antigen-presentation capacities. PDC*line-based vaccine was tested in clinical trials in melanoma and lung cancer. Efficient specific T lymphocyte priming was observed suggesting the efficient migration of injected PDC*line-based vaccine to lymph nodes. Here, we investigated the mechanisms involved in this migration and its regulation. In humanised mice, our results demonstrated the efficient migration of the PDC-based vaccine from blood to lymph nodes and its capacity to prime naive T cells. The expression of CD62L was evaluated following irradiation, which was mandatory in the vaccine manufacturing step and possibly important for its efficacy. CD62L was rapidly shed after irradiation of PDC*line cells and primary PDCs but not of NK-T cells, demonstrating the cell specificity of the mechanism. Our results show that p38 MAP kinase, known to be activated in response to irradiation and ADAM17 metalloprotease are involved in the rapid CD62L shedding. This new pathway could participate to the regulation PDC transmigration through High Endothelial Venules and homing to secondary lymphoid organs in cellular stress conditions.