Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
PLoS One. 2011 Mar 4;6(3):e17631. doi: 10.1371/journal.pone.0017631.
Agonist antibodies against CD137 (4-1BB) on T lymphocytes are used to increase host anti-tumor immunity, but often leading to severe liver injury in treated mice or in patients during clinical trials. Interleukin-6 (IL-6) has been reported to protect hepatocyte death, but the role of IL-6 in protecting chronic T cell-induced liver diseases is not clearly defined due to lack of relevant animal models. We aimed to define the role of IL-6 in CD8+ T cell-mediated liver injury induced by a CD137 agonistic mAb (clone 2A) in mice.
METHODS/PRINCIPAL FINDINGS: We expressed IL-6 in the liver by hydrodynamic gene delivery in mice treated with 2A or control mAb and studied how IL-6 treatment affected host immunity and T cell-mediated liver injury. We found that ectopic IL-6 expression in the liver elevated intrahepatic leukocyte infiltration but prevented CD8+ T cell-mediated liver injury. In IL-6 treated mice, CD8+ T cells proliferation and IFN-γ expression were inhibited in the liver. We discovered that IL-6 increased accumulation of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) in the liver and spleen. These MDSCs had the ability to inhibit T cells proliferation and activation. Finally, we showed that the MDSCs were sufficient and essential for IL-6-mediated protection of anti-CD137 mAb-induced liver injury.
CONCLUSIONS/SIGNIFICANCE: We concluded that IL-6 induced Gr-1+CD11b+ MDSCs in the liver to inhibit T cell-mediated liver injury. The findings have defined a novel mechanism of IL-6 in protecting liver from CD8+ T cell-mediated injury.
针对 T 淋巴细胞上的 CD137（4-1BB）的激动型抗体被用于增强宿主抗肿瘤免疫，但在治疗小鼠或临床试验中的患者中常导致严重肝损伤。白细胞介素 6（IL-6）已被报道可保护肝细胞死亡，但由于缺乏相关的动物模型，IL-6 在保护慢性 T 细胞诱导的肝疾病中的作用尚不清楚。我们旨在确定 IL-6 在 CD137 激动型 mAb（克隆 2A）诱导的小鼠 CD8+T 细胞介导的肝损伤中的作用。
方法/主要发现：我们通过在接受 2A 或对照 mAb 治疗的小鼠中通过液流动力学基因传递在肝脏中表达 IL-6，并研究了 IL-6 治疗如何影响宿主免疫和 CD8+T 细胞介导的肝损伤。我们发现，肝脏中异位表达的 IL-6 会增加肝内白细胞浸润，但可预防 CD8+T 细胞介导的肝损伤。在 IL-6 治疗的小鼠中，CD8+T 细胞在肝脏中的增殖和 IFN-γ 表达受到抑制。我们发现，IL-6 增加了 Gr-1+CD11b+髓源抑制细胞（MDSCs）在肝脏和脾脏中的积累。这些 MDSCs 具有抑制 T 细胞增殖和激活的能力。最后，我们表明 MDSCs 足以并且对于 IL-6 介导的抗 CD137 mAb 诱导的肝损伤保护是必需的。
结论/意义：我们得出结论，IL-6 在肝脏中诱导 Gr-1+CD11b+MDSCs 以抑制 CD8+T 细胞介导的肝损伤。这些发现定义了 IL-6 保护肝脏免受 CD8+T 细胞介导的损伤的新机制。
