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Review
. 2015 Oct 15:22:85.
doi: 10.1186/s12929-015-0194-3.

T cells and reactive oxygen species

Aleksey V Belikov  1 , Burkhart Schraven  2 , Luca Simeoni  3
Affiliations
Review

T cells and reactive oxygen species

Aleksey V Belikov et al. J Biomed Sci. .

Abstract

Reactive oxygen species (ROS) have been long considered simply as harmful by-products of metabolism, which damage cellular proteins, lipids, and nucleic acids. ROS are also known as a weapon of phagocytes, employed against pathogens invading the host. However, during the last decade, an understanding has emerged that ROS also have important roles as signaling messengers in a multitude of pathways, in all cells, tissues, and organs. T lymphocytes are the key players of the adaptive immune response, which both coordinate other immune cells and destroy malignant and virus-infected cells. ROS have been extensively implicated in T-cell hyporesponsiveness, apoptosis, and activation. It has also become evident that the source, the kinetics, and the localization of ROS production all influence cell responses. Thus, the characterization of the precise mechanisms by which ROS are involved in the regulation of T-cell functions is important for our understanding of the immune response and for the development of new therapeutic treatments against immune-mediated diseases. This review summarizes the 30-year-long history of research on ROS in T lymphocytes, with the emphasis on the physiological roles of ROS.

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Figures

Fig. 1
Fig. 1
The redox regulation of T-cell state. Activated phagocytes produce H2O2 via NOX-2. H2O2 either oxidizes thiols (SH-) on the surface of T cells or enters inside T cells. Intracellularly, H2O2 either oxidizes glutathione (GSH) or interferes with DNA synthesis. Activated phagocytes and dendritic cells (DC) secrete cysteine (Cys) to the extracellular space. Cys is taken up by T cells and converted to GSH. GSH keeps surface thiols in the reduced state, neutralizes intracellular H2O2, and enables DNA synthesis. TCR-peptide-MHC interaction leads to the secretion of thioredoxin (TRX) by T cells, DCs, and Tregs. TRX helps to keep surface thiols in the reduced state. Black solid arrow indicates production, black dashed arrows indicate import/export, green solid arrows indicate activation, red bar-headed lines indicate inhibition.
Fig. 2
Fig. 2
ROS in activation-induced T-cell death. TCR triggering leads to the activation of DUOX-1, which produces H2O2 that enhances the activation of ZAP-70 and the formation of the SHP-2-GAB-2-GRB-2-PLCγ-1 complex. MEK-ERK pathway increases O2 •- production by mitochondrial Complex I (CI), which leads to the expression of FasL. Superoxide dismutase (SOD), vitamin E (VitE), and glutathione (GSH) interfere with FasL expression. FasL triggers Fas that initiates apoptosis execution, further enhances O2 •- production by CI, and activates NOX-2. NOX-2 produces H2O2 that enters the cell and activates AKT but inhibits MEK. H2O2 is neutralized by peroxiredoxin (PRX) and GSH. Black solid arrows indicate production, black dashed arrow indicates import, green solid arrows indicate activation, red bar-headed lines indicate inhibition. Skull and bones indicate apoptosis
Fig. 3
Fig. 3
ROS in the activation of primary T cells. The ligation of CD28 leads to the activation of the lipoxygenase pathway (LOX). This enhances the expression of CD25, IL-2, and IL-4. The triggering of TCR leads to increase in O2 •- production by mitochondrial Complex III (CIII). Whether this O2 •- has any function is not clear. Additionally, the ligation of TCR leads to the activation of NOX-2, which produces H2O2 that enters the cell. Inside the cell, H2O2 activates GATA-3 and STAT-6 but inhibits STAT-3. GATA-3 and STAT-6 direct T-cell differentiation towards the Th2 phenotype and the production of IL-4 and IL-5. STAT-3 leads to differentiation into Th17 cells and to IL-17 production. Black solid arrows indicate production, black dashed arrow indicates import, green solid arrows indicate activation, red bar-headed line indicates inhibition
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