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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组织侵入性促炎性T细胞中支架蛋白TKS5的代谢控制

类风湿关节炎（RA）个体中的致病性T细胞浸润非淋巴组织部位，通过细胞外基质进行操纵并形成持久的炎症微结构。在这里，我们发现RA T细胞大量表达足小体支架蛋白TKS5，这使它们能够形成组织浸润性膜结构。TKS5的过度表达受RA T细胞的细胞内代谢环境的调节，特别是糖酵解通量的减少导致ATP和丙酮酸的缺乏。ATP^低丙酮酸^低条件触发脂肪酸生物合成和细胞质脂质小滴的形成。丙酮酸产生的恢复或脂肪酸合成的抑制纠正了体内RA T细胞的组织侵袭性并扭转了他们的促原性行为。因此，对T细胞运动的代谢控制提供了新的机会来干扰T细胞侵入特定组织部位。