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

项目摘要 这项建议的目标是确定PD-L1逆转树突状细胞信号的机制(S (DC)在皮肤感染期间启动DC转运、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从皮肤向皮肤迁移中的主要作用 引流淋巴结节。有趣的是，这种迁移的损失似乎依赖于TLR的刺激或 启动1型干扰素信号的感染。这些发现与PD-L1缓解1型糖尿病的作用是一致的 干扰素信号事件。我们还概述了趋化因子对PD-L1反向信号的要求，但不是S1P， 反应性显示了PD-L1在调节趋化因子信号中的新作用。最后，我们发现T细胞 在没有PD-L1反向信号的情况下，淋巴结中的启动显著减少。然而， T细胞启动中的这些缺陷只有在需要DC运输时才会发生，而不是在抗原直接排出时发生 通过淋巴管和LN，也不会在全身感染之后发生。因此，在这项提案中，我们的目标是 更好地理解树突状细胞迁移过程中PD-L1反向信号的要求 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 控制对趋化因子的反应。最后，我们的目标是解决DC在皮肤中滞留的贡献 由于失去PD-L1信号，导致在牛痘病毒划痕后建立的组织驻留记忆反应。

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.