As the most abundant memory T cells and major source of tumor necrosis factor α in the intestinal mucosa of Crohn’s disease (CD) patients, CD4 tissue-resident memory T (T) cells play a critical role in CD pathogenesis. We investigated the role of metabolic reprogramming in the regulation of proinflammatory and apoptosis-resistant phenotype for CD4 T cells. CD4 T cells were collected from intestinal resection tissues from control and CD patients. Transcriptomic and metabolomic analysis were performed to identify metabolic characteristics of CD4 T cells. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction experiments were used to assess cytokines level in CD4 T cells; activation-induced cell apoptosis rate was evaluated by flow cytometry. Transwell assay and wound healing assay were performed to detect the effect of CD4 T cells on the migration of normal intestinal epithelial cells. Transcriptomic data combined with unbiased metabolomic analysis revealed an increased fatty acid oxidation (FAO) phenotype existed in CD4 T cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4 T cells up-regulated their lipid lipolysis and fatty acid uptake to fuel FAO in CD patients. Mechanistically, the activated nuclear factor kappa B signaling increased transcription of genes involved in lipid lipolysis, fatty acid uptake, and oxidation in CD4 T cells from CD patients Targeting FAO of CD4 T cells reversed their apoptosis-resistant and proinflammatory phenotype in CD patients. CD4 T cells process an accelerated FAO mediated by activated nuclear factor kappa B signaling in CD patients; targeting FAO could reverse their apoptosis-resistant and proinflammatory phenotype. These findings shed a new light on the pathogenic mechanism investigation and novel therapy development in CD patients.

中文翻译：

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脂肪酸氧化促进克罗恩病中 CD4+ 组织驻留记忆 T 细胞的凋亡抵抗和促炎表型

作为克罗恩病（CD）患者肠粘膜中最丰富的记忆T细胞和肿瘤坏死因子α的主要来源，CD4组织驻留记忆T（T）细胞在CD发病机制中发挥着关键作用。我们研究了代谢重编程在调节 CD4 T 细胞促炎和抗凋亡表型中的作用。 CD4 T 细胞是从对照和 CD 患者的肠切除组织中收集的。进行转录组学和代谢组学分析以确定 CD4 T 细胞的代谢特征。采用酶联免疫吸附试验和定量聚合酶链反应实验评估CD4 T细胞中细胞因子的水平；通过流式细胞术评估激活诱导的细胞凋亡率。采用Transwell实验和伤口愈合实验检测CD4 T细胞对正常肠上皮细胞迁移的影响。转录组数据与无偏代谢组学分析相结合揭示了 CD 患者的 CD4 T 细胞中存在脂肪酸氧化 (FAO) 表型增加。脂质组学数据和稳定同位素示踪剂实验表明，CD4 T 细胞上调其脂质脂解和脂肪酸摄取，为 CD 患者的FAO提供能量。从机制上讲，激活的核因子 kappa B 信号传导增加了 CD 患者 CD4 T 细胞中参与脂质脂解、脂肪酸摄取和氧化的基因转录。靶向 CD4 T 细胞的 FAO 逆转了 CD 患者的凋亡抵抗和促炎表型。在 CD 患者中，CD4 T 细胞处理由激活的核因子 kappa B 信号介导的加速FAO；针对FAO的研究可以逆转它们的抗凋亡和促炎症表型。这些发现为克罗恩病患者的致病机制研究和新疗法的开发提供了新的思路。