Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Department of Pediatrics, National School of Tropical Medicine, Baylor College of Medicine, Houston, TX, United States.
Front Immunol. 2018 Jul 26;9:1566. doi: 10.3389/fimmu.2018.01566. eCollection 2018.
Helminth infection induces Th2-biased immune responses and inhibitory/regulatory pathways that minimize excessive inflammation to facilitate the chronic infection of helminth in the host and in the meantime, prevent host hypersensitivity from autoimmune or atopic diseases. However, the detailed molecular mechanisms behind modulation on inflammatory diseases are yet to be clarified. Programmed death 1 (PD-1) is one of the important inhibitory receptors involved in the balance of host immune responses during chronic infection. Here, we used the murine model to examine the role of PD-1 in CD4 T cells in the effects of infection on collagen-induced arthritis (CIA). Mice infected with demonstrated higher expression of PD-1 in the spleen CD4 T cells than those without infection. Mice infected with 2 weeks prior to being immunized with type II collagen displayed lower arthritis incidence and significantly attenuated pathology of CIA compared with those of uninfected mice. The therapeutic effect of infection on CIA was reversed by blocking PD-1 with anti-PD-1 antibody, associated with enhanced Th1/Th17 pro-inflammatory responses and reduced Th2 responses. The role of PD-1 in regulating CD4 T cell differentiation and proliferation during infection was further examined in PD-1 knockout (PD-1) C57BL/6 J mice. Interestingly, -induced alteration of attenuated Th1 and enhanced Th2/regulatory T cell differentiation in wild-type (WT) mice was effectively diminished in PD-1 mice characterized by recovered Th1 cytokine levels, reduced levels of Th2 and regulatory cytokines and CD4CD25Foxp3 cells. Moreover, -induced CD4 T cell proliferation suppression in WT mice was partially restored in PD-1 mice. This study introduces the first evidence that PD-1 plays a critical role in helminth infection-attenuated CIA in a mouse model by regulating the CD4 T cell function, which may provide the new insights into the mechanisms of helminth-induced immunomodulation of host autoimmunity.
寄生虫感染诱导 Th2 偏向性免疫反应和抑制/调节途径，最大限度地减少过度炎症，以促进寄生虫在宿主中的慢性感染，同时防止宿主对自身免疫或特应性疾病产生过敏反应。然而，寄生虫感染对炎症性疾病的调节的详细分子机制尚不清楚。程序性死亡受体 1（PD-1）是慢性感染过程中宿主免疫反应平衡中涉及的重要抑制性受体之一。在这里，我们使用小鼠模型来研究 PD-1 在寄生虫感染对胶原诱导性关节炎（CIA）影响中的脾脏 CD4 T 细胞中的作用。感染寄生虫的小鼠脾脏 CD4 T 细胞中 PD-1 的表达高于未感染的小鼠。与未感染的小鼠相比，在免疫接种 II 型胶原之前 2 周感染寄生虫的小鼠关节炎发病率较低，CIA 病理明显减轻。用抗 PD-1 抗体阻断 PD-1 可逆转寄生虫感染对 CIA 的治疗作用，同时增强 Th1/Th17 促炎反应，减少 Th2 反应。在 PD-1 敲除（PD-1）C57BL/6 J 小鼠中进一步研究了 PD-1 在寄生虫感染过程中调节 CD4 T 细胞分化和增殖的作用。有趣的是，在 PD-1 小鼠中，寄生虫感染诱导的 Th1 减弱和 Th2/调节性 T 细胞增强的分化改变被有效消除，特征为 Th1 细胞因子水平恢复、Th2 和调节性细胞因子水平降低以及 CD4CD25Foxp3 细胞减少。此外，在 PD-1 小鼠中，寄生虫感染诱导的 WT 小鼠 CD4 T 细胞增殖抑制作用部分恢复。这项研究首次表明，PD-1 通过调节 CD4 T 细胞功能，在小鼠模型中寄生虫感染减轻 CIA 中发挥关键作用，这可能为寄生虫诱导宿主自身免疫免疫调节的机制提供新的见解。
