Zhang Zhu-Xu, Wang Shuang, Huang Xuyan, Min Wei-Ping, Sun Hongtao, Liu Weihua, Garcia Bertha, Jevnikar Anthony M
The Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada.
J Immunol. 2008 Dec 1;181(11):7489-98. doi: 10.4049/jimmunol.181.11.7489.
Renal ischemia-reperfusion injury (IRI) can result in acute renal failure with mortality rates of 50% in severe cases. NK cells are important participants in early-stage innate immune responses. However, their role in renal tubular epithelial cell (TEC) injury in IRI is currently unknown. Our data indicate that NK cells can kill syngeneic TEC in vitro. Apoptotic death of TEC in vitro is associated with TEC expression of the NK cell ligand Rae-1, as well as NKG2D on NK cells. In vivo following IRI, there was increased expression of Rae-1 on TEC. FACS analyses of kidney cell preparations indicated a quantitative increase in NKG2D-bearing NK cells within the kidney following IRI. NK cell depletion in wild-type C57BL/6 mice was protective, while adoptive transfer of NK cells worsened injury in NK, T, and B cell-null Rag2(-/-)gamma(c)(-/-) mice with IRI. NK cell-mediated kidney injury was perforin (PFN)-dependent as PFN(-/-) NK cells had minimal capacity to kill TEC in vitro compared with NK cells from wild-type, FasL-deficient (gld), or IFN-gamma(-/-) mice. Taken together, these results demonstrate for the first time that NK cells can directly kill TEC and that NK cells contribute substantially to kidney IRI. NK cell killing may represent an important underrecognized mechanism of kidney injury in diverse forms of inflammation, including transplantation.
肾缺血再灌注损伤（IRI）可导致急性肾衰竭，严重病例的死亡率达50%。自然杀伤（NK）细胞是早期固有免疫反应的重要参与者。然而，它们在IRI所致肾小管上皮细胞（TEC）损伤中的作用目前尚不清楚。我们的数据表明，NK细胞在体外可杀伤同基因TEC。体外TEC的凋亡死亡与TEC表达NK细胞配体Rae-1以及NK细胞上的NKG2D有关。IRI后体内TEC上Rae-1的表达增加。对肾细胞制剂的流式细胞术分析表明，IRI后肾内携带NKG2D的NK细胞数量增加。野生型C57BL/6小鼠体内NK细胞的缺失具有保护作用，而NK细胞的过继转移则加重了IRI的NK、T和B细胞缺陷型Rag2(-/-)γc(-/-)小鼠的损伤。NK细胞介导的肾损伤依赖穿孔素（PFN），因为与来自野生型、FasL缺陷型（gld）或IFN-γ(-/-)小鼠的NK细胞相比，PFN(-/-) NK细胞在体外杀伤TEC的能力极低。综上所述，这些结果首次证明NK细胞可直接杀伤TEC，且NK细胞在很大程度上导致肾IRI。NK细胞杀伤可能是包括移植在内的多种炎症形式中一种重要但未被充分认识的肾损伤机制。
