Imbalance of NKp44+NKp46- and NKp44-NKp46+ Natural Killer Cells in the Intestinal Mucosa of Patients With Crohn's Disease
Imbalance of NKp44+NKp46- and NKp44-NKp46+ Natural Killer Cells in the Intestinal Mucosa of Patients With Crohn's Disease
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DOI：
10.1053/j.gastro.2010.05.040
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发表时间：
2010-09-01
期刊：
影响因子：
29.4
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
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作者：
Takayama, Tetsuro;Kamada, Nobuhiko;Hibi, Toshifumi
背景与目的：产生白细胞介素（IL）-22的粘液自然杀伤（NK）细胞介导小鼠肠道内稳态和炎症。然而，它们在人类炎症性肠病（IBD）发病机制中的作用尚不清楚。我们研究了克罗恩病（CD）患者肠粘膜样本中的肠道NK细胞。方法：我们从IBD患者和非IBD受试者（对照）的肠粘膜样品中分离出固有层NK细胞，并分析了细胞表面分子和细胞因子产生的表达模式。固有层NK细胞和肠道巨噬细胞之间的相互作用进行了检查。研究结果：在对照组的肠粘膜样品中，NKp 44和NKp 46在CD 3（-）CD 56（+）NK细胞上表达差异，NKp 44（+）NKp 46（-）（NKp 44（+））NK细胞表达CD 127和转录因子视黄酸相关孤儿受体C（RORC），并产生IL-22，而NKp 44 NKp 46（+）（NKp 46（+））NK细胞不表达CD 127或RORC，并产生干扰素（IFN）-γ。与对照组或溃疡性结肠炎患者相比，CD患者肠粘膜中NKp 46（+）NK细胞占优势。在与肠道炎症巨噬细胞NKp 46（+）相互作用后，CD患者的NK细胞通过IL-23活化并产生IFN-γ;这种活化需要细胞与细胞接触。结论：CD患者肠黏膜NK细胞NKp 44（+）/NKp 46（+）平衡紊乱。NKp 46（+）NK细胞可能通过产生IFN-γ介导CD的发病。
BACKGROUND & AIMS: Mucosal natural killer (NK) cells that produce interleukin (IL)-22 mediate intestinal homeostasis and inflammation in mice. However, their role in the pathogenesis of human inflammatory bowel diseases (IBDs) is not known. We investigated intestinal NK cells in intestinal mucosa samples of patients with Crohn's disease (CD). METHODS: We isolated lamina propria NK cells from intestinal mucosal samples of patients with IBD and subjects without IBD (controls) and analyzed expression patterns of cell surface molecules and cytokine production. Interactions between lamina propria NK cells and intestinal macrophages were examined. RESULTS: In intestinal mucosa samples from controls, NKp44 and NKp46 were expressed differentially on CD3(-)CD56(+) NK cells, NKp44(+)NKp46(-) (NKp44(+)) NK cells expressed CD127 and the transcription factor retinoic acid-related orphan receptor C (RORC) and produced IL-22 whereas NKp44 NKp46(+) (NKp46(+)) NK cells did not express CD127 or RORC and produced interferon (IFN)-gamma. NKp46(+) NK cells were predominant in intestinal mucosa of patients with CD compared with controls or patients with ulcerative colitis. Upon interaction with intestinal inflammatory macrophages NKp46(+), NK cells from patients with CD were activated via IL-23 and produced IFN-gamma; this activation required cell-to-cell contact. CONCLUSIONS: The balance of NKp44(+)/NKp46(+) NK cells is disrupted in intestinal mucosa of patients with CD. NKp46(+) NK cells might mediate the pathogenesis of CD by producing IFN-gamma.