Allez Matthieu, Tieng Vannary, Nakazawa Atsushi, Treton Xavier, Pacault Vincent, Dulphy Nicolas, Caillat-Zucman Sophie, Paul Pascale, Gornet Jean-Marc, Douay Corinne, Ravet Sophie, Tamouza Ryad, Charron Dominique, Lémann Marc, Mayer Lloyd, Toubert Antoine
Service de Gastroentérologie, Hôpital Saint-Louis, Paris, France; INSERM Unité 662, Hôpital Saint-Louis, Paris, France.
Gastroenterology. 2007 Jun;132(7):2346-58. doi: 10.1053/j.gastro.2007.03.025. Epub 2007 Mar 16.
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, gammadelta T cells, and natural killer cells. We examined the role of MICA-NKG2D interactions in the activation of T lymphocytes in CD.
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.
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.
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.
克罗恩病（CD）是一种炎症性肠病，其特征为对细菌菌群的免疫反应失控，T淋巴细胞过度活化。MICA是一种应激诱导的主要组织相容性复合体相关分子，表达于正常肠上皮细胞（IECs），并被CD8(+) T细胞、γδ 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。
通过流式细胞术分析从活动性炎症性肠病患者和对照者分离的IECs上的MICA表达。分析固有层和外周血淋巴细胞上的NKG2D表达及功能。
CD患者的IECs上MICA表达显著增加，在宏观受累区域表达更高。与对照者及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。CD患者外周和黏膜中具有Th1细胞因子谱且表达穿孔素的CD4(+)NKG2D(+) T细胞增加。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并杀伤表达MICA的靶细胞。CD患者的IECs具有在体外扩增该亚群的能力。CD患者固有层淋巴细胞中的CD4(+)NKG2D(+)高表达白细胞介素-15Rα，白细胞介素-15增加CD4(+)NKG2D(+) T细胞克隆中的NKG2D和DAP10表达。
这些发现突出了MICA-NKG2D在激活CD中具有炎症和细胞毒性特性的独特CD4(+) T细胞亚群中的作用。
