Core Fucosylation on T Cells, Required for Activation of T-Cell Receptor Signaling and Induction of Colitis in Mice, Is Increased in Patients With Inflammatory Bowel Disease
Core Fucosylation on T Cells, Required for Activation of T-Cell Receptor Signaling and Induction of Colitis in Mice, Is Increased in Patients With Inflammatory Bowel Disease
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DOI：
10.1053/j.gastro.2016.03.002
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发表时间：
2016-06-01
期刊：
影响因子：
29.4
通讯作者：
Miyoshi, Eiji
中科院分区：
文献类型：
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作者：
Fujii, Hironobu;Shinzaki, Shinichiro;Miyoshi, Eiji
背景与目的：一个聚焦分子附着在糖蛋白最内层的n -聚糖上（核心聚焦化）可以调节许多生长因子受体和粘附分子的活性。该过程由α 1-6聚焦转移酶（FUT8）催化，是免疫调节所必需的，但目前尚不清楚该过程在疾病发病过程中是否失调。我们研究了核心聚焦化是否调节小鼠t细胞活化和结肠炎的诱导，并在炎症性肠病（IBD）患者中发生改变。方法：从大阪大学医院的患者（8例克罗恩病，4例溃疡性结肠炎，4例无IBD[对照组]）的炎症和非炎症区域收集活检样本。用三硝基苯磺酸诱导Fut8缺陷（Fut8(-/-)）小鼠和Fut8（+/+）窝鼠结肠炎。收集肠道组织并进行组织学分析。收集免疫细胞，并通过凝集素流式细胞术、免疫荧光和逆转录聚合酶链反应分析，以及细胞因子的产生和脂筏馏分中t细胞受体（TCR）的水平。通过向rag2缺陷小鼠腹腔注射CD4(+)CD62L（+）幼稚T细胞，分析T细胞功能。结果：与没有结肠炎的小鼠相比，结肠炎小鼠的T细胞核心聚焦水平升高，IBD患者的炎症粘膜与非炎症组织或对照患者的组织相比，核心聚焦水平升高。与Fut8（+/+）小鼠相比，Fut8（-/-）小鼠结肠炎的严重程度较低，Fut8（-/-）小鼠的T细胞产生较低水平的T-辅助1和2细胞因子。将Fut8(-/-) T细胞过继转移至rag2缺陷小鼠可降低结肠炎的严重程度。与来自Fut8（+/+）小鼠的CD4(+) T细胞相比，来自Fut8（-/-）小鼠的CD4(+) T细胞表达相似水平的TCR和CD28，但这些蛋白不包含核心聚焦。在Fut8（-/-）小鼠的CD4(+) T细胞上形成的TCR复合物在激活后不能正常发出信号，也不能转运到脂筏上。结论：TCR的核心聚焦是t细胞信号传导和炎症细胞因子产生以及小鼠结肠炎诱导所必需的。IBD患者肠组织T细胞中TCR核心聚焦水平升高；作为一种治疗策略，这一过程可能被阻断。
BACKGROUND & AIMS: Attachment of a fucose molecule to the innermost N-glycan in a glycoprotein (core fucosylation) regulates the activity of many growth factor receptors and adhesion molecules. The process is catalyzed by alpha 1-6 fucosyltransferase (FUT8) and required for immune regulation, but it is not clear whether this process is dysregulated during disease pathogenesis. We investigated whether core fucosylation regulates T-cell activation and induction of colitis in mice, and is altered in patients with inflammatory bowel disease (IBD). METHODS: Biopsy samples were collected from inflamed and noninflamed regions of intestine from patients (8 with Crohn's disease, 4 with ulcerative colitis, and 4 without IBD [controls]) at Osaka University Hospital. Colitis was induced in FUT8-deficient (Fut8(-/-)) mice and Fut8(+/+) littermates by administration of trinitrobenzene sulfonic acid. Intestinal tissues were collected and analyzed histologically. Immune cells were collected and analyzed by lectin flow cytometry, immunofluorescence, and reverse-transcription polymerase chain reaction, as well as for production of cytokines and levels of T-cell receptor (TCR) in lipid raft fractions. T-cell function was analyzed by intraperitoneal injection of CD4(+)CD62L(+) naive T cells into RAG2-deficient mice. RESULTS: Levels of core fucosylation were increased on T cells from mice with colitis, compared with mice without colitis, as well as on inflamed mucosa from patients with IBD, compared with their noninflamed tissues or tissues from control patients. Fut8(-/-) mice developed less-severe colitis than Fut8(+/+) mice, and T cells from Fut8(-/-) mice produced lower levels of T-helper 1 and 2 cytokines. Adoptive transfer of Fut8(-/-) T cells to RAG2-deficient mice reduced the severity of colitis. Compared with CD4(+) T cells from Fut8(+/+) mice, those from Fut8(-/-) mice expressed similar levels of TCR and CD28, but these proteins did not contain core fucosylation. TCR complexes formed on CD4(+) T cells from Fut8(-/-) mice did not signal properly after activation and were not transported to lipid rafts. CONCLUSIONS: Core fucosylation of the TCR is required for T-cell signaling and production of inflammatory cytokines and induction of colitis in mice. Levels of TCR core fucosylation are increased on T cells from intestinal tissues of patients with IBD; this process might be blocked as a therapeutic strategy.