Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Department of Natural Sciences, University of Pernambuco, Garanhuns, Brazil.
Front Immunol. 2020 Oct 22;11:574491. doi: 10.3389/fimmu.2020.574491. eCollection 2020.
Cutaneous Leishmaniasis (CL) affects up to one million people every year and treatments are costly and toxic. The regulation of the host immune response is complex and the knowledge of how CD4 T cells are activated and maintained during infection is still limited. Current therapies aim to target programmed cell death (PD)-1 and programmed cell death ligand (PD-L)-1 in order to boost T cell activity. However, the role of the PD-1/PD-L1 axis during infection is still unclear. In this study, we found that patients with active and post-treatment CL displayed different subsets of CD4PD-1 T cells. Accordingly, infected mice upregulated PD-1 on activated CD4 T effector cells and PD-L1 on resident macrophages and infiltrating monocytes at the site of infection. infected mice expressed lower levels of MHCII and higher levels of CD206 on macrophages and monocytes and, more importantly, the lack of PD-L1 contributed to a reduced frequency of CD4Ly6C T effector cells and an increase of CD4Foxp3 regulatory T cells at the site of infection and in draining lymph nodes. Additionally, the lack of PD-L1 was associated with lower production of IL-27 by infiltrating monocytes and lower levels of the Th1 cytokines IFN-γ and TNF-α produced by CD4 T effector cells. mice initially exhibited larger lesions despite having a similar parasite load. Our results describe for the first time how the interruption of the PD-1/PD-L1 axis influences the immune response against CL and suggests that this axis regulates the balance between CD4Ly6C T effector cells and CD4Foxp3 regulatory T cells.
皮肤利什曼病（CL）每年影响多达 100 万人，治疗费用昂贵且具有毒性。宿主免疫反应的调节非常复杂，人们对 CD4 T 细胞在感染过程中如何被激活和维持的了解仍然有限。目前的治疗方法旨在针对程序性细胞死亡（PD）-1 和程序性细胞死亡配体（PD-L）-1，以增强 T 细胞的活性。然而，PD-1/PD-L1 轴在感染过程中的作用仍不清楚。在这项研究中，我们发现活动性和治疗后 CL 患者显示出不同的 CD4PD-1 T 细胞亚群。相应地，感染小鼠在感染部位上调了活化的 CD4 T 效应细胞上的 PD-1 和驻留巨噬细胞和浸润单核细胞上的 PD-L1。感染小鼠在巨噬细胞和单核细胞上表达较低水平的 MHCII 和较高水平的 CD206，更重要的是，缺乏 PD-L1 导致感染部位和引流淋巴结中 CD4Ly6C T 效应细胞的频率降低和 CD4Foxp3 调节性 T 细胞的增加。此外，缺乏 PD-L1 与浸润单核细胞中 IL-27 的产生减少以及 CD4 T 效应细胞中产生的 Th1 细胞因子 IFN-γ和 TNF-α水平降低有关。尽管寄生虫载量相似，但缺乏 PD-L1 的 小鼠最初表现出更大的病变。我们的研究结果首次描述了 PD-1/PD-L1 轴如何影响针对 CL 的免疫反应，并表明该轴调节 CD4Ly6C T 效应细胞和 CD4Foxp3 调节性 T 细胞之间的平衡。
