Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells-specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. ATP^lopyruvate^lo conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoration of pyruvate production or inhibition of fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their proarthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites.

中文翻译：

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组织侵袭性促炎 T 细胞中支架蛋白 TKS5 的代谢控制。


类风湿性关节炎 (RA) 患者中的致病性 T 细胞浸润非淋巴组织部位，穿过细胞外基质并形成持久的炎症微结构。在这里，我们发现 RA T 细胞大量表达足体支架蛋白 TKS5，这使得它们能够形成组织侵袭性膜结构。 TKS5 过度表达受到 RA T 细胞的细胞内代谢环境的调节，具体来说，是通过糖酵解通量的减少来调节，从而导致 ATP 和丙酮酸的缺乏。 ATP^{丙酮酸条件}触发脂肪酸生物合成和细胞质脂滴的形成。恢复丙酮酸的产生或抑制脂肪酸的合成可纠正 RA T 细胞在体内的组织侵袭性并逆转其促关节炎行为。因此，T 细胞运动的代谢控制为干扰 T 细胞侵入特定组织部位提供了新的机会。