Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109-5606, USA.
J Biol Chem. 2010 Dec 31;285(53):41525-32. doi: 10.1074/jbc.M110.189944. Epub 2010 Oct 30.
Naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) suppress proliferation of CD4(+)CD25(-) effector T cells (Teffs) by mechanisms that are not well understood. We have previously demonstrated a novel mechanism of Treg suppression, i.e. interference with extracellular redox remodeling that occurs during activation of T cells by dendritic cells. In this study, we demonstrate that Treg-mediated redox perturbation is antigen-dependent but not antigen-specific, is CTLA-4-dependent, and requires cell-cell contact. Furthermore, we show that Tregs use multiple strategies for extracellular redox remodeling, including diminished GSH synthesis in dendritic cells via decreased expression of γ-glutamylcysteine synthetase, the limiting enzyme for GSH synthesis. Tregs also consume extracellular cysteine and partition it more proficiently to the oxidation product (sulfate), whereas Teffs divert more of the cysteine pool toward protein and GSH synthesis. Tregs appear to block GSH redistribution from the nucleus to the cytoplasm in Teffs, which is abrogated by the addition of exogenous cysteine. Together, these data provide novel insights into modulation of sulfur-based redox metabolism by Tregs, leading to suppression of T cell activation and proliferation.
自然发生的 CD4(+)CD25(+)Foxp3(+)调节性 T 细胞（Tregs）通过尚未完全理解的机制抑制 CD4(+)CD25(-)效应 T 细胞（Teffs）的增殖。我们之前已经证明了 Treg 抑制的一种新机制，即干扰树突状细胞激活 T 细胞过程中外源的氧化还原重塑。在这项研究中，我们证明 Treg 介导的氧化还原扰动是抗原依赖性的，但不是抗原特异性的，依赖 CTLA-4，并需要细胞间接触。此外，我们表明 Tregs 使用多种策略进行细胞外氧化还原重塑，包括通过减少γ-谷氨酰半胱氨酸合成酶（GSH 合成的限速酶）的表达来减少树突状细胞中的 GSH 合成。Tregs 还消耗细胞外半胱氨酸，并更有效地将其分配到氧化产物（硫酸盐）中，而 Teffs 将更多的半胱氨酸池转向蛋白质和 GSH 合成。Tregs 似乎阻止 GSH 从细胞核重新分布到细胞质中，在外源半胱氨酸的添加下这一过程被阻断。这些数据为 Tregs 对基于硫的氧化还原代谢的调节提供了新的见解，导致 T 细胞激活和增殖的抑制。
