The metabolic landscape of thymic T cell development in vivo and in vitro

Although metabolic pathways have been shown to control differentiation and activation inperipheral T cells, metabolic studies on thymic T cell development are still lacking, especially inhuman tissue. In this study, we use transcriptomics and extracellular flux analyses to investigatethe metabolic profiles of primary thymic and in vitro-derived mouse and human thymocytes. Coremetabolic pathways, specifically glycolysis and oxidative phosphorylation, undergo dramaticchanges between the double-negative (DN), double-positive (DP), and mature single-positive (SP)stages in murine and human thymus. Remarkably, despite the absence of the complex multicellularthymic microenvironment, in vitro murine and human T cell development recapitulated thecoordinated decrease in glycolytic and oxidative phosphorylation activity between the DN and DPstages seen in primary thymus. Moreover, by inducing in vitro T cell differentiation from Rag1-/-mouse bone marrow, we show that reduced metabolic activity at the DP stage is independent ofTCR rearrangement. Thus, our findings suggest that highly conserved metabolic transitions arecritical for thymic T cell development.尽管已有研究证实代谢通路可调控外周T细胞的分化与活化，但针对胸腺T细胞发育的代谢研究仍较为匮乏，尤其是在人体组织中。本研究借助转录组学（transcriptomics）与细胞外通量分析（extracellular flux analyses），探究原代胸腺细胞以及体外诱导产生的小鼠和人胸腺细胞的代谢特征。核心代谢通路，尤其是糖酵解（glycolysis）与氧化磷酸化（oxidative phosphorylation），在小鼠和人类胸腺的双阴性（double-negative, DN）、双阳性（double-positive, DP）以及成熟单阳性（single-positive, SP）发育阶段之间发生显著改变。值得注意的是，尽管缺乏复杂的多细胞胸腺微环境，体外培养的小鼠和人T细胞发育过程仍重现了原代胸腺中DN至DP阶段糖酵解与氧化磷酸化活性协同下降的特征。此外，本研究通过从Rag1缺陷型（Rag1-/-）小鼠骨髓中诱导体外T细胞分化，证实DP阶段代谢活性降低与T细胞受体（TCR）重排无关。综上，本研究结果表明高度保守的代谢转变对于胸腺T细胞发育至关重要。