Department of Internal Medicine, University of Genoa and San Martino Hospital of Genoa, 16132-Italy.
Eur J Immunol. 2009 Dec;39(12):3459-68. doi: 10.1002/eji.200939728.
Soluble HLA class I (sHLA-I) molecules can regulate survival of NK cells and their anti-tumor killing activity. Herein, we have analysed whether interaction of sHLA-I with CD8 and/or different isoforms of killer Ig-like receptors (KIR) induced secretion of transforming growth factor (TGF)-beta1. CD8+KIR- NK cell clones secreted TGF-beta1 upon the interaction of sHLA-I with CD8 molecule. sHLA-Cw4 or sHLA-Cw3 alleles engaging inhibitory isoforms of KIR, namely KIR2DL1 or KIR2DL2, strongly downregulated TGF-beta1 production elicited through CD8. On the other hand, sHLA-Cw4 or sHLA-Cw3 alleles induced secretion of TGF-beta1 by ligation of stimulatory KIR2DS1 or KIR2DS2 isoforms. TGF-beta1 strongly reduced NK cell-mediated tumor cell lysis and production of pro-inflammatory cytokines such as TNF-alpha and IFN-gamma. Also, TGF-beta1 inhibited NK cell cytolysis induced by the engagement of stimulatory receptors including NKG2D, DNAM1, 2B4, CD69, NKp30, NKp44 and NKp46. The IL-2-dependent surface upregulation of some of these receptors was prevented by TGF-beta1. Furthermore, TGF-beta1 hampered IL-2-induced NK cell proliferation but not IL-2-mediated rescue from apoptosis of NK cells. Depletion of TGF-beta1 restored all the NK cell-mediated functional activities analysed. Taken together these findings suggest that sHLA-I antigens may downregulate the NK cell-mediated innate response by inducing TGF-beta1 release.
可溶性 HLA Ⅰ类分子（sHLA-I）可调节 NK 细胞的存活及其抗肿瘤杀伤活性。在此，我们分析了 sHLA-I 与 CD8 和/或不同的杀伤免疫球蛋白样受体（KIR）亚型相互作用是否诱导转化生长因子（TGF）-β1 的分泌。CD8+KIR-NK 细胞克隆在 sHLA-I 与 CD8 分子相互作用时分泌 TGF-β1。与抑制性 KIR 亚型（即 KIR2DL1 或 KIR2DL2）结合的 sHLA-Cw4 或 sHLA-Cw3 等位基因强烈下调通过 CD8 引发的 TGF-β1 产生。另一方面，sHLA-Cw4 或 sHLA-Cw3 等位基因通过与刺激性 KIR2DS1 或 KIR2DS2 亚型的结合诱导 TGF-β1 的分泌。TGF-β1 强烈抑制 NK 细胞介导的肿瘤细胞裂解和促炎细胞因子如 TNF-α和 IFN-γ的产生。此外，TGF-β1 抑制包括 NKG2D、DNAM1、2B4、CD69、NKp30、NKp44 和 NKp46 在内的刺激受体诱导的 NK 细胞细胞毒性。TGF-β1 可阻止某些这些受体的 IL-2 依赖性表面上调。此外，TGF-β1 阻碍 IL-2 诱导的 NK 细胞增殖，但不阻碍 IL-2 介导的 NK 细胞凋亡的挽救。TGF-β1 的耗竭恢复了分析的所有 NK 细胞介导的功能活性。这些发现表明，sHLA-I 抗原通过诱导 TGF-β1 释放可能下调 NK 细胞介导的先天反应。
