CD4+ T cells contribute critically to a protective immune response during intestinal infections, but have also been implicated in the aggravation of intestinal inflammatory pathology. Previous studies suggested that T helper type (Th)1 and Th17 cells depend on de novo fatty acid (FA) synthesis for their development and effector function. Here, we report that T-cell-specific targeting of the enzyme acetyl-CoA carboxylase 1 (ACC1), a major checkpoint controlling FA synthesis, impaired intestinal Th1 and Th17 responses by limiting CD4+ T-cell expansion and infiltration into the lamina propria in murine models of colitis and infection-associated intestinal inflammation. Importantly, pharmacological inhibition of ACC1 by the natural compound soraphen A mirrored the anti-inflammatory effects of T-cell-specific targeting, but also enhanced susceptibility toward infection with C. rodentium. Further analysis revealed that deletion of ACC1 in RORγt+ innate lymphoid cells (ILC), but not dendritic cells or macrophages, decreased resistance to infection by interfering with IL-22 production and intestinal barrier function. Together, our study suggests pharmacological targeting of ACC1 as an effective approach for metabolic immune modulation of T-cell-driven intestinal inflammatory responses, but also reveals an important role of ACC1-mediated lipogenesis for the function of RORγt+ ILC.

中文翻译：

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靶向细胞脂肪酸合成会限制 T 辅助细胞和先天性淋巴样细胞在肠道炎症和感染期间的功能。

CD4+ T 细胞在肠道感染期间对保护性免疫反应起着关键作用，但也与肠道炎症病理学的恶化有关。以前的研究表明，T 辅助型 (Th)1 和 Th17 细胞的发育和效应功能依赖于脂肪酸 (FA) 的从头合成。在这里，我们报告了乙酰辅酶 A 羧化酶 1 (ACC1) 的 T 细胞特异性靶向，这是一个控制 FA 合成的主要检查点，通过限制 CD4+ T 细胞扩增和浸润到固有层中来损害肠道 Th1 和 Th17 反应结肠炎和感染相关肠道炎症的小鼠模型。重要的是，天然化合物 soraphen A 对 ACC1 的药理学抑制反映了 T 细胞特异性靶向的抗炎作用，但也增强了对 C. rodentium 感染的易感性。进一步分析表明，RORγt+ 先天性淋巴样细胞 (ILC) 中 ACC1 的缺失，而不是树突状细胞或巨噬细胞，通过干扰 IL-22 的产生和肠屏障功能降低了对感染的抵抗力。总之，我们的研究表明 ACC1 的药理学靶向是 T 细胞驱动的肠道炎症反应的代谢免疫调节的有效方法，但也揭示了 ACC1 介导的脂肪生成对 RORγt+ ILC 功能的重要作用。