Johansson Sofia E, Hall Håkan, Björklund Jens, Höglund Petter
Microbiology and Tumor Biology Center, Karolinska Institutet, 17 177 Stockholm, Sweden.
Int Immunol. 2004 Jan;16(1):1-11. doi: 10.1093/intimm/dxh002.
NK cells represent a link between innate and adaptive immunity, and may play a role in regulating autoimmune disorders. We have characterized the NK cell population in non-obese diabetic (NOD) mice. The percentage and absolute numbers of NK cells were similar in NOD and control MHC-matched B6.g7 mice. However, the capacity of NOD NK cells to mediate natural cytotoxicity as well as FcR- and Ly49D-mediated killing was compromised in vitro, suggesting a defect affecting multiple activation pathways. The defect was neither linked to the NK gene complex nor to the MHC, as determined by comparison with mice congenic for these regions. Introducing the beta(2)-microglobulin mutation on the NOD background further impaired NK cell function, showing that the compromised cytotoxic capacity in these two strains arises from two independent mechanisms. In vivo rejection responses against tumor cells and against MHC class I-deficient spleen cells were decreased in naive NOD recipients, but restored in mice pre-activated with tilorone, a potent activator of NK cells. In addition, killing of some tumor targets was restored in vitro after activation of NK cells with IL-12 plus IL-18 or with IFN-alpha/beta, but not with IL-2. Interestingly, natural killing of RMA-S targets by NOD NK cells could not be restored in vitro, indicating that restoration of killing capacity was only partial. Our data suggest a severe, but partially restorable, killing defect in NOD NK cells, affecting activation through several pathways.
自然杀伤(NK)细胞是先天性免疫和适应性免疫之间的纽带,可能在调节自身免疫性疾病中发挥作用。我们已对非肥胖型糖尿病(NOD)小鼠的NK细胞群体进行了特征描述。NOD小鼠和对照的主要组织相容性复合体(MHC)匹配的B6.g7小鼠中,NK细胞的百分比和绝对数量相似。然而,NOD NK细胞介导自然细胞毒性以及FcR和Ly49D介导的杀伤的能力在体外受损,提示存在影响多种激活途径的缺陷。与这些区域的同源基因小鼠比较后确定,该缺陷既不与NK基因复合体相关,也不与MHC相关。在NOD背景上引入β2-微球蛋白突变进一步损害了NK细胞功能,表明这两个品系中细胞毒性能力受损源于两种独立机制。在未活化的NOD受体小鼠中,对肿瘤细胞和MHC I类缺陷脾细胞的体内排斥反应降低,但在用NK细胞的强效激活剂泰洛龙预激活的小鼠中得以恢复。此外,用白细胞介素(IL)-12加IL-18或干扰素(IFN)-α/β激活NK细胞后,某些肿瘤靶标的杀伤在体外得以恢复,但用IL-2则不能。有趣的是,NOD NK细胞对RMA-S靶标的自然杀伤在体外无法恢复,表明杀伤能力的恢复只是部分性的。我们的数据提示NOD NK细胞存在严重但部分可恢复的杀伤缺陷,影响多种途径的激活。