A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity
A Novel Role for IL-6 Receptor Classic Signaling: Induction of RORγt+Foxp3+ Tregs with Enhanced Suppressive Capacity
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DOI：
10.1681/asn.2019020118
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发表时间：
2019-08-01
影响因子：
13.6
通讯作者：
Steinmetz, Oliver M.
中科院分区：
文献类型：
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作者：
Hagenstein, Julia;Melderis, Simon;Steinmetz, Oliver M.
背景 阻断 IL-6 受体 (IL-6R) 的新疗法最近已上市，并成功用于治疗关节炎等炎症性疾病。目前尚不清楚 IL-6 阻滞剂是否可以帮助肾脏炎症患者。 方法 为了更多地了解 CD4(+) T 细胞固有的 IL-6R 信号转导的复杂作用，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，这是新月体肾小球肾炎的小鼠模型。我们在报告小鼠中使用过继转移实验和研究来分析免疫反应和 Treg 亚群。结果 小鼠 CD4(+) T 细胞中 IL-6Ra 信号传导的缺乏损害了促炎 Th17 细胞的生成，但令人惊讶的是并没有改善 GN 的病程。相比之下，通过限制 T 效应细胞的 IL-6Ra 缺乏并排除 Tregs，肾损伤显着减少。对 Tregs 的详细研究表明，尽管 IL-6Ra 缺乏，但 IL-10 的产生没有改变。然而，在体内和体外，IL-6Ra经典信号传导诱导ROR gamma t(+)Foxp3(+)双阳性Tregs (biTregs)，其携带运输受体CCR6并具有有效的免疫调节特性。事实上，IL-6Ra 的缺乏显着降低了 Treg 的体外抑制能力。最后，含有IL-6Ra(-/-) Tregs 的T 细胞的过继转移导致小鼠GN 严重恶化。结论我们的数据完善了旧的范例，即IL-6 增强Th17 反应并抑制Tregs。我们在这里提供的证据表明，T 细胞固有的 IL-6Ra 经典信号传导确实诱导 Th17 细胞的生成，但同时高度免疫抑制 ROR gamma t(+)biTregs。这些结果主张谨慎行事，并表明针对 GN 的 IL-6 导向疗法需要针对细胞类型。
Background 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.Methods 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.Results 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 productiondespite IL-6Ra deficiency. However, in vivo and in vitro, IL-6Ra classic signaling induced ROR gamma t(+)Foxp3(+) double-positive Tregs (biTregs), which carry the trafficking receptor CCR6 and have potent immunoregulatory properties. Indeed, lack of IL-6Ra significantly reduced Treg in vitro suppressive capacity. Finally, adoptive transfer of T cells containing IL-6Ra(-/-) Tregs resulted in severe aggravation of GN in mice.Conclusions 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 ROR gamma t(+)biTregs. These results advocate caution and indicate that IL-6-directed therapies for GN need to be cell-type specific.