Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge

Abstract

Reactive oxygen species (ROS) are critical in a broad spectrum of cellular processes including signaling, tumor progression, and innate immunity. The essential nature of ROS signaling in the immune systems of Drosophila and zebrafish has been demonstrated; however, the role of ROS, if any, in mammalian adaptive immune system development and function remains unknown. The current work provides the first clear demonstration that thymus specific elevation of mitochondrial superoxide (O2·−) disrupts normal T-cell development to impair function of the mammalian adaptive immune system. To assess the effect of elevated mitochondrial superoxide in the developing thymus, we used a T-cell specific knockout of manganese superoxide dismutase (i.e. SOD2) and have thus established a murine model to examine the role of mitochondrial superoxide in T-cell development. Conditional loss of SOD2 led to increased superoxide, apoptosis, and developmental defects in the T-cell population resulting in immunodeficiency and susceptibility to influenza A virus (IAV), H1N1. This phenotype was rescued with mitochondrially targeted superoxide scavenging drugs. These new findings demonstrate that loss of regulated levels of mitochondrial superoxide lead to aberrant T-cell development and function, and further suggest that manipulations of mitochondrial superoxide levels may significantly alter clinical outcomes resulting from viral infection.

N-acetyl-l-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV)

“…There are studies that demonstrate that oxidative stress increases the susceptibility to viral infection for RSV and influenza viruses [19,40]. Our data indicate that after virus infection there is an increase of intracellular levels of H 2 O 2 and a decrease of intracellular thiols.…”

“…An oxidative environment is necessary for influenza replication to [17]. Elevation of mitochondrial superoxide increases susceptibility to influenza infection in mice [18] and in A549 [19]. ROS induction after influenza infection increases the expression of pro-inflammatory molecules like IL8, IL6, CCL5 or CXCL10 [20].…”

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

“…However, at a later stage (4-8 h after TCR stimulation), increased MnSOD levels diminish the oxidative signal (probably due to an out-titration effect) (Kaminski et al 2012a). Reports by Case et al (2011) and Maric et al (2009) support a crucial role of MnSOD for T-cell homeostasis. T-cell-specific MnSOD knock-out results in increased mitochondrial superoxide anion levels, enhanced thymocyte apoptosis, decreased number of peripheral T cells and impaired clearance of an influenza virus.…”

“…T-cell effector response (Christie et al 2012), thymocyte differentiation (Case et al 2011), graft-versus-host disease (Gatza et al 2011) or progression of experimental autoimmune encephalomyelitis (EAE) (Michalek et al 2011). Importantly, mitochondria and the cellular metabolic state are decisive for differentiation of T-cell subsets and development of memory and regulatory phenotypes (for further reading, please refer to (Gerriets and Rathmell 2012;Wang and Green 2012).…”

“…T-cell-specific MnSOD knock-out results in increased mitochondrial superoxide anion levels, enhanced thymocyte apoptosis, decreased number of peripheral T cells and impaired clearance of an influenza virus. Both thymocytes and peripheral T cells appear hyperactivated (Case et al 2011). Decreased MnSOD activity and content in mouse T cells deficient in the interferon (IFN)-c-inducible lysosomal thiol reductase (Gilt -/-) lead to enhanced TCR-triggered ERK activation and higher intracellular superoxide levels (Maric et al 2009).…”