Laboratory of Oncology, G. Gaslini Scientific Institute, Genoa, Italy.
Blood. 2011 Nov 24;118(22):5840-50. doi: 10.1182/blood-2011-05-352393. Epub 2011 Oct 11.
Soluble HLA-G (sHLA-G) inhibits natural killer (NK) cell functions. Here, we investigated sHLA-G-mediated modulation of (1) chemokine receptor and NK receptor expression and function and (2) cytokine and chemokine secretion in CD56bright and CD56dim NK cells. sHLA-G-treated or untreated peripheral blood (PB) and tonsil NK cells were analyzed for chemokine receptor and NK receptor expression by flow cytometry. sHLA-G down-modulated (1) CXCR3 on PB and tonsil CD56bright and CD56dim, (2) CCR2 on PB and tonsil CD56bright, (3) CX3CR1 on PB CD56dim, (4) CXCR5 on tonsil CD56dim, and (5) CD94/NKG2A on PB and tonsil CD56brigh) and CD56dim NK cells. Such sHLA-G-mediated down-modulations were reverted by adding anti-HLA-G or anti-ILT2 mAbs. sHLA-G inhibited chemotaxis of (1) PB NK cells toward CXCL10, CXCL11, and CX3CL1 and (2) PB CD56bright NK cells toward CCL2 and CXCL10. IFN-γ secretion induced by NKp46 engagement was inhibited by NKG2A engagement in untreated but not in sHLA-G-treated NK cells. sHLA-G up-regulated secretion of (1) CCL22 in CD56bright and CD56dim and (2) CCL2, CCL8, and CXCL2-CXCL3 in CD56dim PB NK cells. Signal transduction experiments showed sHLA-G-mediated down-modulation of Stat5 phosphorylation in PB NK cells. In conclusion, our data delineated novel mechanisms of sHLA-G-mediated inhibition of NK-cell functions.
可溶性 HLA-G（sHLA-G）抑制自然杀伤（NK）细胞功能。在这里，我们研究了 sHLA-G 介导的（1）趋化因子受体和 NK 受体表达和功能以及（2）CD56bright 和 CD56dim NK 细胞中细胞因子和趋化因子分泌的调节。通过流式细胞术分析 sHLA-G 处理或未处理的外周血（PB）和扁桃体 NK 细胞的趋化因子受体和 NK 受体表达。sHLA-G 下调（1）PB 和扁桃体 CD56bright 和 CD56dim 的 CXCR3，（2）PB 和扁桃体 CD56bright 的 CCR2，（3）PB CD56dim 的 CX3CR1，（4）扁桃体 CD56dim 的 CXCR5，和（5）PB 和扁桃体 CD56bright 和 CD56dim NK 细胞的 CD94/NKG2A。这种 sHLA-G 介导的下调可以通过添加抗-HLA-G 或抗-ILT2 mAb 来逆转。sHLA-G 抑制（1）PB NK 细胞向 CXCL10、CXCL11 和 CX3CL1 的趋化作用和（2）PB CD56bright NK 细胞向 CCL2 和 CXCL10 的趋化作用。在未经处理的 NK 细胞中，NKG2A 结合抑制了 NKp46 结合诱导的 IFN-γ 分泌，但在 sHLA-G 处理的 NK 细胞中没有抑制。sHLA-G 上调（1）CD56bright 和 CD56dim 的 CCL22 和（2）CD56dim PB NK 细胞的 CCL2、CCL8 和 CXCL2-CXCL3 的分泌。信号转导实验表明，sHLA-G 介导了 PBNK 细胞中 Stat5 磷酸化的下调。总之，我们的数据描绘了 sHLA-G 介导的 NK 细胞功能抑制的新机制。
