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

项目摘要 该提案的目的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细胞引发和T细胞编程。我们的研究 已经概述了PD-L1反向信号传导在控制DC从皮肤迁移到皮肤中的主要作用。 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信号的感染。这些发现与PD-L1缓解1型糖尿病的作用一致。 IFN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，但不是S1 P， 这表明PD-L1在调节趋化因子信号传导中的新作用。最后，我们发现T细胞 在没有PD-L1反向信号传导的情况下，淋巴结中的引发显著降低。然而，在这方面， T细胞引发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 也不会在全身性感染后通过淋巴管到达LN。因此，在本提案中，我们的目标是 更好地理解PD-L1反向信号在树突状细胞迁移中的要求， 毛细淋巴管我们还旨在了解PD-L1的细胞外和细胞内结构域如何 控制对趋化因子的反应。最后，我们的目标是解决DC保留在皮肤中的贡献 这是由于在牛痘划痕后建立的组织驻留记忆应答的PD-L1信号传导丢失引起的。

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.