Victorino Francisco, Sojka Dorothy K, Brodsky Kelley S, McNamee Eoin N, Masterson Joanne C, Homann Dirk, Yokoyama Wayne M, Eltzschig Holger K, Clambey Eric T
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045; Immunology Graduate Program, University of Colorado School of Medicine, Aurora, CO 80045;
Rheumatology Division, Washington University School of Medicine, St. Louis, MO 63110;
J Immunol. 2015 Nov 15;195(10):4973-85. doi: 10.4049/jimmunol.1500651. Epub 2015 Oct 9.
NK cells are innate lymphoid cells important for immune surveillance, identifying and responding to stress, infection, and/or transformation. Whereas conventional NK (cNK) cells circulate systemically, many NK cells reside in tissues where they appear to be poised to locally regulate tissue function. In the present study, we tested the contribution of tissue-resident NK (trNK) cells to tissue homeostasis by studying ischemic injury in the mouse kidney. Parabiosis experiments demonstrate that the kidney contains a significant fraction of trNK cells under homeostatic conditions. Kidney trNK cells developed independent of NFIL3 and T-bet, and they expressed a distinct cell surface phenotype as compared with cNK cells. Among these, trNK cells had reduced asialo-GM1 (AsGM1) expression relative to cNK cells, a phenotype observed in trNK cells across multiple organs and mouse strains. Strikingly, anti-AsGM1 Ab treatment, commonly used as an NK cell-depleting regimen, resulted in a robust and selective depletion of cNKs, leaving trNKs largely intact. Using this differential depletion, we tested the relative contribution of cNK and trNK cells in ischemic kidney injury. Whereas anti-NK1.1 Ab effectively depleted both trNK and cNK cells and protected against ischemic/reperfusion injury, anti-AsGM1 Ab preferentially depleted cNK cells and failed to protect against injury. These data demonstrate unanticipated specificity of anti-AsGM1 Ab depletion on NK cell subsets and reveal a new approach to study the contributions of cNK and trNK cells in vivo. In total, these data demonstrate that trNK cells play a key role in modulating local responses to ischemic tissue injury in the kidney and potentially other organs.
自然杀伤细胞（NK细胞）是先天性淋巴细胞，对免疫监视、识别并应对应激、感染和/或细胞转化起着重要作用。传统NK（cNK）细胞在全身循环，而许多NK细胞驻留在组织中，似乎随时准备对组织功能进行局部调节。在本研究中，我们通过研究小鼠肾脏的缺血性损伤，测试了组织驻留NK（trNK）细胞对组织稳态的作用。联体共生实验表明，在稳态条件下，肾脏含有相当一部分trNK细胞。肾脏trNK细胞的发育独立于NFIL3和T-bet，与cNK细胞相比，它们表达独特的细胞表面表型。其中，trNK细胞相对于cNK细胞，去唾液酸GM1（AsGM1）表达降低，这是在多个器官和小鼠品系的trNK细胞中观察到的一种表型。引人注目的是，通常用作NK细胞清除方案的抗AsGM1抗体处理，导致cNK细胞大量且选择性地减少，而trNK细胞基本保持完整。利用这种差异清除，我们测试了cNK细胞和trNK细胞在缺血性肾损伤中的相对作用。抗NK1.1抗体有效地清除了trNK细胞和cNK细胞，并预防了缺血/再灌注损伤，而抗AsGM1抗体优先清除cNK细胞，未能预防损伤。这些数据证明了抗AsGM1抗体对NK细胞亚群清除具有意外的特异性，并揭示了一种在体内研究cNK细胞和trNK细胞作用的新方法。总的来说，这些数据表明trNK细胞在调节肾脏及可能其他器官对缺血性组织损伤的局部反应中起关键作用。
