University of Antwerp, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (VAXINFECTIO), Laboratory of Experimental Hematology, Antwerp, Belgium.
PLoS One. 2012;7(12):e51851. doi: 10.1371/journal.pone.0051851. Epub 2012 Dec 28.
Dendritic cells (DCs) are the quintessential antigen-presenting cells of the human immune system and play a prime role in coordinating innate and adaptive immune responses, explaining the strong and still growing interest in their application for cancer immunotherapy. Much current research in the field of DC-based immunotherapy focuses on optimizing the culture conditions for in vitro DC generation in order to assure that DCs with the best possible immunogenic qualities are being used for immunotherapy. In this context, monocyte-derived DCs that are alternatively induced by interleukin-15 (IL-15 DCs) have attracted recent attention due to their superior immunostimulatory characteristics. In this study, we show that IL-15 DCs, in addition to potent tumor antigen-presenting function, possess tumoricidal potential and thus qualify for the designation of killer DCs. Notwithstanding marked expression of the natural killer (NK) cell marker CD56 on a subset of IL-15 DCs, we found no evidence of a further phenotypic overlap between IL-15 DCs and NK cells. Allostimulation and antigen presentation assays confirmed that IL-15 DCs should be regarded as bona fide myeloid DCs not only from the phenotypic but also from the functional point of view. Concerning their cytotoxic activity, we demonstrate that IL-15 DCs are able to induce apoptotic cell death of the human K562 tumor cell line, while sparing tumor antigen-specific T cells. The cytotoxicity of IL-15 DCs is predominantly mediated by granzyme B and, to a small extent, by tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand (TRAIL) but is independent of perforin, Fas ligand and TNF-α. In conclusion, our data provide evidence of a previously unappreciated role for IL-15 in the differentiation of human monocytes towards killer DCs. The observation that IL-15 DCs have killer DC capacity lends further support to their implementation in DC-based immunotherapy protocols.
树突状细胞 (DCs) 是人类免疫系统中典型的抗原呈递细胞，在协调先天和适应性免疫反应中发挥着重要作用，这也解释了人们对其在癌症免疫治疗中应用的强烈兴趣。目前，基于 DC 的免疫治疗领域的许多研究都集中在优化体外生成 DC 的培养条件上，以确保使用具有最佳免疫原性的 DC 进行免疫治疗。在这种情况下，白细胞介素-15（IL-15）诱导的单核细胞来源的 DC 由于其优越的免疫刺激特性而引起了人们的关注。在这项研究中，我们表明，IL-15 DC 除了具有强大的肿瘤抗原呈递功能外，还具有杀肿瘤作用，因此有资格被称为杀伤性 DC。尽管在 IL-15 DC 的一个亚群上表达了明显的自然杀伤 (NK) 细胞标志物 CD56，但我们没有发现 IL-15 DC 和 NK 细胞之间存在进一步表型重叠的证据。同种刺激和抗原呈递测定证实，从表型和功能的角度来看，IL-15 DC 应被视为真正的髓样 DC。关于其细胞毒性活性，我们证明 IL-15 DC 能够诱导人 K562 肿瘤细胞系的凋亡性细胞死亡，同时保留肿瘤抗原特异性 T 细胞。IL-15 DC 的细胞毒性主要由颗粒酶 B 介导，在较小程度上由肿瘤坏死因子-α（TNF-α）相关凋亡诱导配体 (TRAIL) 介导，但独立于穿孔素、Fas 配体和 TNF-α。总之，我们的数据提供了 IL-15 在人类单核细胞向杀伤性 DC 分化中发挥作用的证据。观察到 IL-15 DC 具有杀伤性 DC 能力，这进一步支持了将其应用于基于 DC 的免疫治疗方案。
