Abstract：
The PD-1-PD-L1 immune checkpoint helps to maintain self-tolerance and prevent the development of autoimmune diseases. Immune checkpoint inhibitors are successful immunotherapeutics for several cancers, but responding patients can develop immune-mediated adverse events. It is well established that PD-1 regulates CD4 and CD8 T-cell responses, but its role in controlling the activation of pathogenic γδ T cells is less clear. Here we examined the role of PD-1 in regulating γδ T cells in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We found that PD-1 was highly expressed on CD27- Vγ4 γδ T cells in the lymph node (LN) and CNS of mice with EAE. Treatment of mice with anti-PD-1 significantly augmented IL-17A-producing CD27- Vγ4 γδ T cells in the LN and CNS and enhanced the severity of EAE. The exacerbating effect of anti-PD-1 on EAE was lost in Tcrd-/- mice. Conversely, ligation of PD-1 suppressed Il17a and Rorc gene expression and IL-17A production by purified Vγ4 γδ T cells stimulated via the TCR, but not with IL-1β and IL-23. Our study demonstrates that PD-1 regulates TCR-activated CD27- Vγ4 γδ T cells, but that cytokine-activated IL-17A producing γδ T cells escape the regulatory effects of the PD-1-PD-L1 pathway.
摘要：
PD-1-PD-L1免疫检查点有助于维持自身耐受性并预防自身免疫性疾病的发展。免疫检查点抑制剂是几种癌症的成功免疫治疗剂，但有反应的患者会发生免疫介导的不良事件。已经确定PD-1调节CD4和CD8T细胞反应，但其在控制致病性γδT细胞活化中的作用尚不清楚。在这里，我们研究了PD-1在实验性自身免疫性脑脊髓炎（EAE）中调节γδT细胞的作用，多发性硬化症的小鼠模型。我们发现PD-1在EAE小鼠的淋巴结（LN）和CNS中的CD27-Vγ4γδT细胞上高表达。用抗PD-1处理小鼠显着增强了LN和CNS中产生IL-17A的CD27-Vγ4γδT细胞，并增强了EAE的严重程度。抗PD-1对EAE的加重作用在Tcrd-/-小鼠中丧失。相反，PD-1的连接通过TCR刺激的纯化的Vγ4γδT细胞抑制了Il17a和Rorc基因表达和IL-17A的产生，但与IL-1β和IL-23无关。我们的研究表明，PD-1调节TCR激活的CD27-Vγ4γδT细胞，但是产生细胞因子激活的IL-17A的γδT细胞逃避了PD-1-PD-L1途径的调节作用。
