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

Abstract

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-κB- 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.

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

“…Nagy et al (2003) reported that TCR/CD28 co-stimulation leads to a rapid (4 h) mitochondrial hyperpolarisation as well as nitric oxide and ROS generation. Our experimental results clearly demonstrate a crucial role for a mitochondriaoriginated oxidative signal in T-cell activation-induced NF-jB-and AP-1-dependent transcription (IL-2, IL-4, IL-8, IjBa, CD95L and MnSOD genes) as well as in a CD95L-dependent activation-induced T-cell death (AICD) (Gulow et al 2005;Kaminski et al 2007Kaminski et al , 2010Kaminski et al , 2012a.…”

“…Later, TCR-triggered ROS production was directly demonstrated (Devadas et al 2002;Gulow et al 2005;Gutscher et al 2008;Hildeman et al 1999;Sekkat et al 1988;Tatla et al 1999;Williams and Henkart 1996). Many studies, including ours, have shown that a transient generation of low physiologically relevant levels of ROS, i.e., a hydrogen peroxide-mediated oxidative signal, facilitates triggering of oxidation-dependent transcription factors, NF-jB and AP-1 (Devadas et al 2002;Kaminski et al 2010Kaminski et al , 2012aTatla et al 1999). Full transcription of interleukin (IL)-2, IL-4 and CD95 ligand (L) genes was only possible when the Iono-introduced Ca 2?…”

Mitochondrial ROS in the prohypertensive immune response

“…It has been shown that mitochondrial superoxide is crucial for cytokine production in T-cells. SOD2 overexpression results in decreased IL-2, a cytokine required for T-cell survival and proliferation (6). Mitochondrial superoxide was also shown to regulate mitochondrial glycerol-3-phosphate dehydrogenase in T-cells.…”

“…In other disease conditions, lymphocytes, key players in development of hypertension, relay on mitochondrial superoxide to maintain their functions (9). Overexpression of mitochondrial SOD prevents T-cell activation and cytokine production (6). Naïve immune cells retained in the organism, while maintaining low metabolic profile, are designed to wait for a signal initiating their immediate response.…”

Mitochondria Regulate Neutrophil Activation by Generating ATP for Autocrine Purinergic Signaling

“…To assess mitochondrial function in more detail, we used DHR 123 to monitor ROS production, which occurs as a byproduct of mitochondrial ATP synthesis (15)(16)(17). In the presence of ROS, non-fluorescent DHR 123 is oxidized to fluorescent rhodamine 123, making it possible to assess mitochondrial activity in real time using a fluorescence microscope.…”