Beider Katia, Nagler Arnon, Wald Ori, Franitza Suzanna, Dagan-Berger Michal, Wald Hanna, Giladi Hilla, Brocke Stefan, Hanna Jacob, Mandelboim Ofer, Darash-Yahana Merav, Galun Eithan, Peled Amnon
Hadassah University Hospital, Gene Therapy Institute, PO Box 12000, Jerusalem, Israel.
Blood. 2003 Sep 15;102(6):1951-8. doi: 10.1182/blood-2002-10-3293. Epub 2003 May 1.
Human natural killer (NK) and NK T cells play an important role in allogeneic bone marrow (BM) transplantation and graft-versus-leukemia (GVL) effect. The mechanisms by which these cells home to the BM and spleen are not well understood. Here we show that treatment of these cells with pertussis toxin and neutralizing antibodies to the chemokine receptor CXCR4 inhibited homing of the cells to the BM, but not the spleen, of NOD/SCID mice. The retention of NK and NK T cells within the spleen and BM was dependent on Galphai signaling and CXCR4 function. The chemokine receptors CXCR4 and CXCR3 are expressed predominantly on the cell surface of NK T cells. Following activation with interleukin-2 (IL-2), the levels of CXCR4 on NK and NK T cells decreased significantly. Treatment of cells with IL-2 inhibited their migration in response to CXCL12 and their homing and retention in the BM and spleen of NOD/SCID mice. In contrast to CXCR4, the expression levels of the chemokine receptor CXCR3 and the migration of cells in response to CXCL9 and CXCL10 increased after IL-2 treatment. Thus, down-regulation of CXCR4 and up-regulation of CXCR3 may direct the trafficking of cells to the site of inflammation, rather than to hematopoietic organs, and therefore may limit their alloreactive potential.
人类自然杀伤（NK）细胞和NK T细胞在异基因骨髓（BM）移植及移植物抗白血病（GVL）效应中发挥着重要作用。这些细胞归巢至骨髓和脾脏的机制尚未完全明确。在此，我们发现用百日咳毒素处理这些细胞以及使用趋化因子受体CXCR4的中和抗体，可抑制细胞归巢至NOD/SCID小鼠的骨髓，但不影响其归巢至脾脏。NK细胞和NK T细胞在脾脏和骨髓中的滞留依赖于Gαi信号传导和CXCR4功能。趋化因子受体CXCR4和CXCR3主要表达于NK T细胞的细胞表面。用白细胞介素-2（IL-2）激活后，NK细胞和NK T细胞表面的CXCR4水平显著降低。用IL-2处理细胞可抑制其对CXCL12的迁移反应以及在NOD/SCID小鼠骨髓和脾脏中的归巢与滞留。与CXCR4相反，IL-2处理后趋化因子受体CXCR3的表达水平以及细胞对CXCL9和CXCL10的迁移反应增加。因此，CXCR4的下调和CXCR3的上调可能会引导细胞迁移至炎症部位而非造血器官，从而可能限制它们的同种异体反应潜能。
