Department of Immunology, UConn Health, 263 Farmington Avenue, Farmington, CT, 06030, USA.
Institute for Systems Genomics, UConn Health, 400 Farmington Avenue, Farmington, CT, 06030, USA.
Mucosal Immunol. 2018 Sep;11(5):1398-1407. doi: 10.1038/s41385-018-0037-0. Epub 2018 Jun 15.
Immune-mediated lung is considered the result of an exacerbated innate injury immune response, although a role for adaptive lymphocytes is emerging. αβ T cells specific for S. aureus enterotoxin A orchestrate a Tγδ17 response during lung injury. However, the mechanism driving IL-17 production is unclear. Here, we show a role for IL-2 triggering IL-17 production by lung granular γδ T cells as IL-17 synthesis and neutrophil recruitment was reduced by IL-2 blocking mAbs in vitro and in vivo. Mass cytometry analysis revealed that lung γδ T cells responded directly to IL-2 as evident from STAT5 phosphorylation and RoRγt expression. IL-2 receptor blocking mAbs and JAK inhibition impaired STAT5 phosphorylation and IL-17 release. Moreover, inhalation of S. aureus enterotoxin A induced IL-2 secretion and caspase-1-dependent IL-1β activation to drive IL-17 production. This T-cell-mediated inflammasome-dependent IL-17 response is maximum when lung Tγδ17 cells were sequentially stimulated first with IL-2 then IL-1β. Interestingly, when IL-2 is given therapeutically to cancer patients it carries a known risk of lung injury that is largely indistinguishable from that seen in sepsis. Hence, this novel mechanism reveals therapeutic targets treating both acute lung injury and high-dose IL-2 toxicity in cancer.
免疫介导性肺部疾病被认为是先天损伤免疫反应加剧的结果，尽管适应性淋巴细胞的作用正在显现。针对金黄色葡萄球菌肠毒素 A 的αβ T 细胞在肺部损伤过程中协调 Tγδ17 反应。然而，驱动 IL-17 产生的机制尚不清楚。在这里，我们展示了 IL-2 触发肺部颗粒状 γδ T 细胞产生 IL-17 的作用，因为 IL-2 阻断 mAb 在体外和体内减少了 IL-17 的合成和中性粒细胞的募集。质谱细胞术分析显示，肺部 γδ T 细胞直接对 IL-2 作出反应，这从 STAT5 磷酸化和 RoRγt 表达上可以明显看出。IL-2 受体阻断 mAb 和 JAK 抑制会损害 STAT5 磷酸化和 IL-17 的释放。此外，金黄色葡萄球菌肠毒素 A 的吸入会诱导 IL-2 的分泌和 caspase-1 依赖性的 IL-1β 激活，从而驱动 IL-17 的产生。当肺部 Tγδ17 细胞首先被 IL-2 然后被 IL-1β 序贯刺激时，这种 T 细胞介导的炎症小体依赖性的 IL-17 反应最大。有趣的是，当 IL-2 被给予癌症患者进行治疗时，它会带来已知的肺部损伤风险，这与脓毒症中观察到的风险非常相似。因此，这种新的机制揭示了治疗急性肺损伤和癌症中高剂量 IL-2 毒性的治疗靶点。
