School of Dentistry, Division of Foundational Sciences, University of Alberta, Edmonton, AB, Canada.
Department of Oncology, University of Alberta, Edmonton, AB, Canada.
Front Immunol. 2023 Mar 16;14:1131379. doi: 10.3389/fimmu.2023.1131379. eCollection 2023.
Natural killer (NK) cells are a potent innate source of cytokines and cytoplasmic granules. Their effector functions are tightly synchronized by the balance between the stimulatory and inhibitory receptors. Here, we quantified the proportion of NK cells and the surface presence of Galectin-9 (Gal-9) from the bone marrow, blood, liver, spleen, and lungs of adult and neonatal mice. We also examined the effector functions of Gal-9NK cells compared with their Gal-9 counterparts. Our results revealed that Gal-9NK cells are more abundant in tissues, in particular, in the liver than in the blood and bone marrow. We found Gal-9 presence was associated with enhanced cytotoxic effector molecules granzyme B (GzmB) and perforin expression. Likewise, Gal-9 expressing NK cells displayed greater IFN-γ and TNF-α expression than their negative counterparts under hemostatic circumstances. Notably, the expansion of Gal-9NK cells in the spleen of mice infected with implies that Gal-9NK cells may provide a protective role against infection. Similarly, we found the expansion of Gal-9NK cells in the spleen and tumor tissues of melanoma B16-F10 mice. Mechanistically, our results revealed the interaction of Gal-9 with CD44 as noted by their co-expression/co-localization. Subsequently, this interaction resulted in enhanced expression of Phospho-LCK, ERK, Akt, MAPK, and mTOR in NK cells. Moreover, we found Gal-9NK cells exhibited an activated phenotype as evidenced by increased CD69, CD25, and Sca-1 but reduced KLRG1 expression. Likewise, we found Gal-9 preferentially interacts with CD44 in human NK cells. Despite this interaction, we noted a dichotomy in terms of effector functions in NK cells from COVID-19 patients. We observed that the presence of Gal-9 on NK cells resulted in a greater IFN-γ expression without any changes in cytolytic molecule expression in these patients. These observations suggest differences in Gal-9NK cell effector functions between mice and humans that should be considered in different physiological and pathological conditions. Therefore, our results highlight the important role of Gal-9 CD44 in NK cell activation, which suggests Gal-9 is a potential new avenue for the development of therapeutic approaches to modulate NK cell effector functions.
自然杀伤 (NK) 细胞是细胞因子和细胞质颗粒的强大先天来源。它们的效应功能通过刺激和抑制受体之间的平衡紧密同步。在这里，我们定量测定了成年和新生小鼠骨髓、血液、肝脏、脾脏和肺部 NK 细胞的比例和 Galectin-9 (Gal-9) 的表面存在。我们还比较了 Gal-9NK 细胞与 Gal-9 对照细胞的效应功能。我们的结果表明，Gal-9NK 细胞在组织中更为丰富，特别是在肝脏中，而在血液和骨髓中则较少。我们发现 Gal-9 的存在与增强的细胞毒性效应分子颗粒酶 B (GzmB) 和穿孔素的表达有关。同样，在止血条件下，表达 Gal-9 的 NK 细胞比其阴性对照细胞表达更高水平的 IFN-γ 和 TNF-α。值得注意的是，Gal-9NK 细胞在感染 小鼠脾脏中的扩增表明，Gal-9NK 细胞可能在抗感染中发挥保护作用。同样，我们在黑色素瘤 B16-F10 小鼠的脾脏和肿瘤组织中发现了 Gal-9NK 细胞的扩增。从机制上讲，我们的结果表明 Gal-9 与 CD44 的相互作用，如它们的共表达/共定位所表明的那样。随后，这种相互作用导致 NK 细胞中 Phospho-LCK、ERK、Akt、MAPK 和 mTOR 的表达增强。此外，我们发现 Gal-9NK 细胞表现出激活表型，表现为 CD69、CD25 和 Sca-1 增加，而 KLRG1 表达减少。同样，我们发现 Gal-9 优先与人类 NK 细胞中的 CD44 相互作用。尽管存在这种相互作用，但我们注意到 COVID-19 患者 NK 细胞在效应功能方面存在二分法。我们观察到，NK 细胞上 Gal-9 的存在导致 IFN-γ 表达增加，而这些患者的细胞毒性分子表达没有任何变化。这些观察结果表明 Gal-9NK 细胞效应功能在小鼠和人类之间存在差异，在不同的生理和病理条件下应考虑这些差异。因此，我们的结果强调了 Gal-9 CD44 在 NK 细胞激活中的重要作用，这表明 Gal-9 是一种潜在的新途径，可用于开发调节 NK 细胞效应功能的治疗方法。
