Manganese superoxide dismutase: A regulator of T cell activation-induced oxidative signaling and cell death

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• 作者：Marcin Miko艂aj Kami艅ski^a ; ¹ ; ^{m.kaminski@dkfz.de} ; Daniel Rö ; th^a ; ¹ ; Sabine Sass^a ; Sven Wolfgang Sauer^b ; Peter Heinrich Krammer^a ; Karsten Gü ; low^a ; ^{k.guelow@dkfz.de}
• 关键词：ROS ; Reactive oxygen species ; IL-2 ; interleukin 2 ; CD95L/FASL/APO-1 ; CD95 ligand ; AICD ; activation-induced cell death ; MnSOD/SOD2 ; manganese superoxide dismutase ; TCR ; T cell receptor
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2012
• 期刊代码：20_01674889
• 类别：bio
• 出版时间：May, 2012
• 卷：1823
• 期：5
• 页码：1041-1052
• 文件大小：628 K

摘要

Mitochondrial reactive oxygen species (ROS) are indispensible for T cell activation-induced expression of interleukin 2 (IL-2) and CD95 ligand (CD95L, FasL/Apo-1L) genes, and in turn, for CD95L-mediated activation-induced cell death (AICD). Here, we show that manganese superoxide dismutase (MnSOD/SOD2), a major mitochondrial antioxidative enzyme, constitutes an important control switch in the process of activation-induced oxidative signal generation in T cells. Analysis of the kinetics of T cell receptor (TCR)-triggered ROS production revealed a temporal association between higher MnSOD abundance/activity and a shut-down phase of oxidative signal generation. Transient or inducible MnSOD overexpression abrogated T cell activation-triggered mitochondrial ROS production as well as NF-魏B- and AP-1-mediated transcription. Consequently, lowered expression of IL-2 and CD95L genes resulted in decreased IL-2 secretion and CD95L-dependent AICD. Moreover, upregulation of the mitochondrial MnSOD level is dependent on oxidation-sensitive transcription and not on the increase of mitochondrial mass. Thus, MnSOD-mediated negative feedback regulation of activation-induced mitochondrial ROS generation exemplifies a process of retrograde mitochondria-to-nucleus communication. Our finding underlines the critical role for MnSOD and mitochondria in the regulation of human T cell activation.