Chaudhry Umer I, Kingham T Peter, Plitas George, Katz Steven C, Raab Jesse R, DeMatteo Ronald P
Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 2006 Nov 1;66(21):10497-504. doi: 10.1158/0008-5472.CAN-06-1908.
Natural killer dendritic cells (NKDC) are a novel subtype of dendritic cells with natural killer (NK) cell properties. IFN-gamma is a pleiotropic cytokine that plays an important role in the innate immune response to tumors. Based on our previous finding that the combination of Toll-like receptor 9 ligand CpG and interleukin (IL)-4 stimulates NKDC to produce IFN-gamma, we hypothesized that NKDC are the major IFN-gamma-producing dendritic cell subtype and may play a significant role in the host antitumor response. We found that under several conditions in vitro and in vivo NKDC accounted for the majority of IFN-gamma production by murine spleen CD11c(+) cells. IL-18 alone induced NKDC to secrete IFN-gamma, and the combination of IL-18 and CpG resulted in a synergistic increase in IFN-gamma production, both in vitro and in vivo. NK cells made 26-fold less IFN-gamma under the same conditions in vitro, whereas dendritic cells produced a negligible amount. The mechanism of IFN-gamma secretion by NKDC depended on IL-12. NKDC selectively proliferated in vitro and in vivo in response to the combination of IL-18 and CpG. Systemic treatment with IL-18 and CpG reduced the number of B16F10 melanoma lung metastases. The mechanism depended on NK1.1(+) cells, as their depletion abrogated the effect. IL-18 and CpG activated NKDC provided greater tumor protection than NK cells in IFN-gamma(-/-) mice. Thus, NKDC are the major dendritic cell subtype to produce IFN-gamma. The combined use of IL-18 and CpG is a viable strategy to potentiate the antitumor function of NKDC.
自然杀伤树突状细胞（NKDC）是具有自然杀伤（NK）细胞特性的新型树突状细胞亚型。干扰素-γ是一种多效性细胞因子，在对肿瘤的先天性免疫反应中起重要作用。基于我们之前的发现，即Toll样受体9配体CpG与白细胞介素（IL）-4联合可刺激NKDC产生干扰素-γ，我们推测NKDC是产生干扰素-γ的主要树突状细胞亚型，可能在宿主抗肿瘤反应中发挥重要作用。我们发现，在体外和体内的几种条件下，NKDC占小鼠脾脏CD11c(+)细胞产生的干扰素-γ的大部分。单独的IL-18可诱导NKDC分泌干扰素-γ，IL-18与CpG联合在体外和体内均可导致干扰素-γ产生的协同增加。在相同的体外条件下，NK细胞产生的干扰素-γ减少26倍，而树突状细胞产生的量可忽略不计。NKDC分泌干扰素-γ的机制依赖于IL-12。NKDC在体外和体内对IL-18与CpG的联合反应而选择性增殖。用IL-18和CpG进行全身治疗可减少B16F10黑色素瘤肺转移灶的数量。其机制依赖于NK1.1(+)细胞，因为它们的缺失消除了这种作用。在干扰素-γ(-/-)小鼠中，IL-18和CpG激活的NKDC比NK细胞提供了更强的肿瘤保护作用。因此，NKDC是产生干扰素-γ的主要树突状细胞亚型。联合使用IL-18和CpG是增强NKDC抗肿瘤功能的可行策略。
