CD4+NKG2D+ T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions
CD4+NKG2D+ T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions
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DOI：
10.1053/j.gastro.2007.03.025
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发表时间：
2007-06-01
期刊：
影响因子：
29.4
通讯作者：
Toubert, Antoine
中科院分区：
文献类型：
--
作者：
Allez, Matthieu;Tieng, Vannary;Toubert, Antoine
背景与目的：克罗恩病（CD）是一种炎症性肠病，其特征是对细菌菌群的免疫反应失控，T淋巴细胞过度激活。MICA是应激诱导的主要组织相容性复合物相关分子，在正常肠上皮细胞（IECs）上表达，并被CD8(+) T细胞、γ δ T细胞和自然杀伤细胞上的nkg2d激活受体识别。我们研究了MICA- nkg2d相互作用在CD中T淋巴细胞活化中的作用。方法：通过流式细胞术分析从活动性炎症性肠病患者和对照组分离的IECs中MICA的表达。分析NKG2D在固有层和外周血淋巴细胞中的表达及功能。结果：MICA在CD的IECs中表达明显升高，且在宏观受损伤区域表达较高。与对照组和溃疡性结肠炎患者相比，CD患者固有层中表达NKG2D的CD4(+) T细胞亚群增加。CD4(+)NKG2D(+) T细胞具有Th1细胞因子谱并表达穿孔素，在CD的外周和粘膜中增加。CD4(+)NKG2D(+) T细胞克隆通过MICA-NKG2D相互作用具有功能活性，产生干扰素γ并杀死表达MICA的靶标。来自乳糜泻患者的IECs在体外具有扩展该亚群的能力。CD患者CD4(+)NKG2D（+）固有层淋巴细胞高表达白细胞介素- 15r α，白细胞介素-15增加了CD4(+)NKG2D(+) t细胞克隆中NKG2D和DAP10的表达。结论：这些发现强调了MICA-NKG2D在CD中具有炎症和细胞毒性的CD4(+) T细胞的独特亚群的激活中的作用。
Background & Aims: Crohn's disease (CD) is an inflammatory bowel disease characterized by uncontrolled immune responses to bacterial flora, with excessive activation of T lymphocytes. MICA is a stress-induced major histocompatibility complex-related molecule expressed on normal intestinal epithelial cells (IECs) and recognized by the NKG2D-activating receptor on CD8(+) T cells, gamma delta T cells, and natural killer cells. We examined the role of MICA-NKG2D interactions in the activation of T lymphocytes in CD. Methods: MICA expression was analyzed by flow cytometry on IECs isolated from patients with active inflammatory bowel disease and controls. NKG2D expression and function were analyzed on lamina propria and peripheral blood lymphocytes. Results: MICA expression was significantly increased on IECs in CD, with higher expression in macroscopically involved areas. A subset of CD4(+) T cells expressing NKG2D was increased in the lamina propria from patients with CD compared with controls and patients with ulcerative colitis. CD4(+)NKG2D(+) T cells with a Th1 cytokine profile and expressing perforin were increased in the periphery and in the mucosa in CD. CD4(+)NKG2D(+) T-cell clones were functionally active through MICA-NKG2D interactions, producing interferon-gamma and killing targets expressing MICA. IECs from patients with CD had the ability to expand this subset in vitro. CD4(+)NKG2D(+) lamina propria lymphocytes from patients with CD highly expressed interleukin-15R alpha, and interleukin-15 increased NKG2D and DAP10 expression in CD4(+)NKG2D(+) T-cell clones. Conclusions: These findings highlight the role of MICA-NKG2D in the activation of a unique subset of CD4(+) T cells with inflammatory and cytotoxic properties in CD.