Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA; Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China.
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
Immunol Lett. 2022 Jul;247:13-21. doi: 10.1016/j.imlet.2022.03.008. Epub 2022 May 11.
Follicular helper T (T) cells are expanded in systemic lupus erythematosus (SLE), where they are required for production of high affinity autoantibodies. A better understanding of the mechanisms that regulate the differentiation of T cells is critical. Naïve T cells from lupus-prone B6.NZM2410.Sle1.Sle2.Sle3 (TC) mice showed an intrinsic higher capacity to differentiate into T cells. Metabolic reprogramming is a vital regulatory mechanism for T cell differentiation, but how metabolic pathways contribute to T cell expansion in SLE remains elusive. Here we show that glycolysis, mTOR signaling, FAO, and the activity of complex V of the electron transport chain support T lineage commitment. Blocking complex I uniquely decreased the expansion of T cells from lupus-prone mice, and inhibition of some pathways had a greater effect in lupus-prone than control T cells. However, blocking glutaminolysis, complex III and ADP/ATP translocase did not affect T cell expansion. Together, our results identified novel intrinsic metabolic requirements for T cell differentiation, and further defined the differential metabolic pathways that support the expansion of T cells in lupus-prone mice. Together, our data indicates the crucial but distinct roles for metabolic pathways in T cell differentiation and provide a comprehensive experimental basis for fully understanding the precise roles of distant metabolic signaling in regulating the T cell differentiation.
滤泡辅助 T(T)细胞在系统性红斑狼疮(SLE)中扩增，在 SLE 中，它们是产生高亲和力自身抗体所必需的。更好地理解调节 T 细胞分化的机制是至关重要的。狼疮易感 B6.NZM2410.Sle1.Sle2.Sle3(TC)小鼠的幼稚 T 细胞显示出内在的更高分化为 T 细胞的能力。代谢重编程是 T 细胞分化的重要调节机制，但代谢途径如何促进 SLE 中的 T 细胞扩增仍不清楚。在这里，我们表明糖酵解、mTOR 信号、FAO 和电子传递链复合物 V 的活性支持 T 细胞系的承诺。阻断复合物 I 可特异性降低狼疮易感小鼠 T 细胞的扩增，而某些途径在狼疮易感 T 细胞中的抑制作用大于对照 T 细胞。然而，阻断谷氨酰胺分解、复合物 III 和 ADP/ATP 易位酶并不影响 T 细胞的扩增。总之，我们的结果确定了 T 细胞分化的新的内在代谢要求，并进一步定义了支持狼疮易感小鼠 T 细胞扩增的不同代谢途径。总之，我们的数据表明代谢途径在 T 细胞分化中起着关键但不同的作用，并为全面理解远距离代谢信号在调节 T 细胞分化中的精确作用提供了全面的实验基础。
