Najar Mehdi, Fayyad-Kazan Mohammad, Meuleman Nathalie, Bron Dominique, Fayyad-Kazan Hussein, Lagneaux Laurence
Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.
Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Bruxelles, Belgium.
J Cell Commun Signal. 2018 Dec;12(4):673-688. doi: 10.1007/s12079-018-0448-4. Epub 2018 Jan 19.
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are multipotent progenitor cells that have shown promise for several different therapeutic applications. As they are able to modulate the function of several types of immune cells, BM-MSCs are highly important in the field of cell-based immunotherapy. Understanding BM-MSC-natural killer (NK) cell interactions is crucial for improving their therapeutic efficiency. Here, we observed that the type of NK cell-activating cytokine (e.g., IL-2, IL-12, IL-15 and IL-21) strongly influenced the outcomes of their interactions with BM-MSCs. The expression patterns of the ligands (CD112, CD155, ULPB-3) and receptors (LAIR, NCR) mediating the cross-talk between BM-MSCs and NK cells were critically modulated following co-culture. BM-MSCs partially impaired NK cell proliferation but up-regulated their secretion of IFN-γ and TNF-α. As they are cytotoxic, activated NK cells induced the killing of BM-MSCs. Indeed, BM-MSCs triggered the degranulation of NK cells and increased their release of perforin and granzymes. Interestingly, activated NK cells induced ROS generation within BM-MSCs that caused their decreased viability and reduced expression of serpin B9. Collectively, our observations reveal that BM-MSC-NK cell interactions may impact the immunobiology of both cell types. The therapeutic potential of BM-MSCs will be significantly improved once these issues are well characterized.
骨髓来源的间充质基质细胞（BM-MSCs）是多能祖细胞，已在多种不同的治疗应用中展现出前景。由于它们能够调节多种免疫细胞的功能，BM-MSCs在基于细胞的免疫治疗领域非常重要。了解BM-MSC与自然杀伤（NK）细胞的相互作用对于提高其治疗效率至关重要。在此，我们观察到NK细胞激活细胞因子的类型（例如，IL-2、IL-12、IL-15和IL-21）强烈影响它们与BM-MSCs相互作用的结果。共培养后，介导BM-MSCs与NK细胞之间相互作用的配体（CD112、CD155、ULPB-3）和受体（LAIR、NCR）的表达模式受到关键调节。BM-MSCs部分损害NK细胞增殖，但上调其IFN-γ和TNF-α的分泌。由于活化的NK细胞具有细胞毒性，它们诱导了BM-MSCs的杀伤。实际上，BM-MSCs触发了NK细胞的脱颗粒，并增加了其穿孔素和颗粒酶的释放。有趣的是，活化的NK细胞诱导BM-MSCs内ROS的产生，导致其活力下降和丝氨酸蛋白酶抑制剂B9的表达降低。总体而言，我们的观察结果表明，BM-MSC-NK细胞相互作用可能会影响这两种细胞类型的免疫生物学。一旦这些问题得到充分表征，BM-MSCs的治疗潜力将得到显著提高。
