Regulatory innate lymphoid cells suppress innate immunity and reduce renal ischemia/reperfusion injury

Innate lymphoid cells are a recently recognized group of immune cells with critical roles in tissue homeostasis and inflammation. Regulatory innate lymphoid cells are a newly identified subset of innate lymphoid cells, which play a suppressive role in the innate immune response, favoring the resolution of intestinal inflammation. However, the expression and role of regulatory innate lymphoid cells in kidney has not been reported. Here, we show that regulatory innate lymphoid cells are present in both human and mouse kidney, express similar surface markers and form a similar proportion of total kidney innate lymphoid cells. Regulatory innate lymphoid cells from kidney were expanded in vitro with a combination of IL-2, IL-7 and transforming growth factor-beta. These cells exhibited immunosuppressive effects on innate immune cells via secretion of IL-10 and transforming growth factor-beta. Moreover, treatment with IL-2/IL-2 antibody complexes (IL-2C) promoted expansion of regulatory innate lymphoid cells in vivo, and prevent renal ischemia/reperfusion injury in Rag-/- mice that lack adaptive immune cells including Tregs. Depletion of regulatory innate lymphoid cells with anti-CD25 antibody abolished the beneficial effects of IL-2C in the Rag-/- mice. Adoptive transfer of ex vivo expanded regulatory innate lymphoid cells improved renal function and attenuated histologic damage when given before or after induction of ischemia/reperfusion injury in association with reduction of neutrophil infiltration and induction of reparative M2 macrophages in kidney. Thus, our study shows that regulatory innate lymphoid cells suppress innate renal inflammation and ischemia/reperfusion injury.

固有淋巴细胞是最近被发现的一组免疫细胞，在组织内稳态和炎症中起关键作用。调节性固有淋巴细胞是固有淋巴细胞中一个新确定的亚群，其在固有免疫应答中起抑制作用，有利于肠道炎症的消退。然而，调节性固有淋巴细胞在肾脏中的表达及作用尚未见报道。在此，我们表明调节性固有淋巴细胞存在于人和小鼠的肾脏中，表达相似的表面标志物，并且在肾脏固有淋巴细胞总数中所占比例相似。肾脏调节性固有淋巴细胞在白细胞介素 - 2、白细胞介素 - 7和转化生长因子 - β的共同作用下可在体外扩增。这些细胞通过分泌白细胞介素 - 10和转化生长因子 - β对固有免疫细胞表现出免疫抑制作用。此外，白细胞介素 - 2/白细胞介素 - 2抗体复合物（IL - 2C）治疗可促进体内调节性固有淋巴细胞的扩增，并预防缺乏包括调节性T细胞在内的适应性免疫细胞的Rag - / - 小鼠的肾缺血/再灌注损伤。用抗CD25抗体清除调节性固有淋巴细胞可消除IL - 2C在Rag - / - 小鼠中的有益作用。在诱导缺血/再灌注损伤之前或之后给予体外扩增的调节性固有淋巴细胞进行过继转移，可改善肾功能并减轻组织学损伤，同时减少肾脏中的中性粒细胞浸润并诱导修复性M2巨噬细胞产生。因此，我们的研究表明调节性固有淋巴细胞可抑制肾脏固有炎症和缺血/再灌注损伤。