III. Department of Medicine and.
Medical Faculty, Institute of Biochemistry and Molecular Biology II, Heinrich-Heine University, Dusseldorf, Germany.
J Am Soc Nephrol. 2019 Aug;30(8):1439-1453. doi: 10.1681/ASN.2019020118. Epub 2019 Jul 16.
New therapies blocking the IL-6 receptor (IL-6R) have recently become available and are successfully being used to treat inflammatory diseases like arthritis. Whether IL-6 blockers may help patients with kidney inflammation currently remains unknown.
To learn more about the complex role of CD4 T cell-intrinsic IL-6R signaling, we induced nephrotoxic nephritis, a mouse model for crescentic GN, in mice lacking T cell-specific IL-6Ra. We used adoptive transfer experiments and studies in reporter mice to analyze immune responses and Treg subpopulations.
Lack of IL-6Ra signaling in mouse CD4 T cells impaired the generation of proinflammatory Th17 cells, but surprisingly did not ameliorate the course of GN. In contrast, renal damage was significantly reduced by restricting IL-6Ra deficiency to T effector cells and excluding Tregs. Detailed studies of Tregs revealed unaltered IL-10 production despite IL-6Ra deficiency. However, and , IL-6Ra classic signaling induced RORγtFoxp3 double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra Tregs resulted in severe aggravation of GN in mice.
Our data refine the old paradigm, that IL-6 enhances Th17 responses and suppresses Tregs. We here provide evidence that T cell-intrinsic IL-6Ra classic signaling indeed induces the generation of Th17 cells but at the same time highly immunosuppressive RORγt biTregs. These results advocate caution and indicate that IL-6-directed therapies for GN need to be cell-type specific.
最近出现了一些阻断白细胞介素 6 受体 (IL-6R) 的新疗法，并且这些疗法在治疗关节炎等炎症性疾病方面取得了成功。然而，目前尚不清楚 IL-6 阻滞剂是否对肾脏炎症患者有帮助。
为了更深入地了解 CD4 T 细胞固有 IL-6R 信号的复杂作用，我们在缺乏 T 细胞特异性 IL-6Ra 的小鼠中诱导了肾毒性肾炎，这是一种新月体肾炎的小鼠模型。我们使用过继转移实验和报告基因小鼠研究来分析免疫反应和 Treg 亚群。
缺乏 IL-6Ra 信号在小鼠 CD4 T 细胞中损害了促炎性 Th17 细胞的生成，但令人惊讶的是，这并没有改善 GN 的病程。相比之下，通过将 IL-6Ra 缺陷限制在 T 效应细胞中并排除 Treg 细胞，肾脏损伤显著减轻。对 Treg 细胞的详细研究表明，尽管缺乏 IL-6Ra，但 IL-10 的产生并没有改变。然而，和，IL-6Ra 经典信号诱导了 RORγtFoxp3 双阳性 Treg（biTreg）的产生，biTreg 细胞表达趋化因子受体 CCR6，具有很强的免疫调节特性。事实上，缺乏 IL-6Ra 显著降低了 Treg 的抑制能力。最后，过继转移含有 IL-6Ra Treg 的 T 细胞导致小鼠 GN 严重恶化。
我们的数据完善了旧的范式，即 IL-6 增强 Th17 反应并抑制 Treg。我们在此提供证据表明，T 细胞固有 IL-6Ra 经典信号确实诱导了 Th17 细胞的产生，但同时也诱导了高度免疫抑制的 RORγt biTreg。这些结果表明需要谨慎，并表明针对 GN 的 IL-6 靶向治疗需要针对特定的细胞类型。
