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Mitochondrial ROS and T Cell Activation
C H A P T E R
5 Mitochondrial ROS and T Cell Activation Karthik B. Mallilankaraman National University of Singapore, Singapore, Singapore
5.1. INTRODUCTION Stimulation of the T cell receptor (TCR) by foreign antigens through antigen-presenting cells (APCs) drives the T cells into rapid proliferation and differentiation, wherein naive T cells expand clonally and differentiate to become effector T cells. Traditionally, TCR stimulation results in PLC-γ1 induction that causes T cells to proliferate and differentiate via Inositol 3,4,5-triphosphate (IP3) mediated rise in cytosolic Ca21 and downstream activation of Ca21-dependent transcription factors. These transcription factors are nuclear factors of activated T cells (NFAT), NF-κB and AP-1 and are well established to control the T cell activation-induced gene expression. While NFAT is predominantly Ca21 dependent, NF-κB and AP-1 are promiscuous and can be activated by low physiological levels of reactive oxygen species (ROS) that is generated transiently during the T cell activation process (Droge, 2002; Kaminski et al., 2010, 2012) Thus, oxidative signal can be considered to be indispensable for T cell activation (Droge, 2002; Kaminski et al., 2010; Devadas et al., 2002). Together with the Ca21 influx, low levels of ROS constitutes the nominal requirement for activation-induced expression of genes such as interleukin 2 (IL-2), a major autocrine factor for T cell proliferation (Meuer et al., 1984), IL-4 and CD95L (Kaminski et al., 2007, 2010; Devadas et al., 2002; Gulow et al., 2005). During T cell activation, ROS is produced from different sources such as NADPH oxidases (NOX2, DUOX2), lipoxygenases (Jackson et al., 2004; Kwon et al., 2010; Los et al., 1995), and the mitochondrial respiratory chain (Kaminski et al., 2007, 2010, 2012; Yi et al., 2006). T cell activation is a highly energy demanding process, where mitochondrial ATP production plays a pivotal role. To meet the high energy demand during the activation process, T cells increase their mitochondrial biogenesis and respiratory chain activity (D’Souza et al., 2007). Increased mitochondrial respiration results in the rapid increase in mitochondrial ROS (Grayson et al., 2003). Activation of T cells is immediately followed by clonal expansion through rapid proliferation and differentiation. While physiological levels of ROS play an important role in T cell activation, uncontrolled high-levels of ROS affect the clonal expansion and result in removal of activated cells (Hildeman et al., 1999). A fine balance between these two events of activation and expansion requires optimal levels of ROS. ROS also drives apoptosis in activated T cells either via activation-induced cell death (AICD) or activated cell autonomous death (ACAD) (Meuer et al., 1984; D’Souza et al., 2007; Hildeman et al., 1999; Brenner et al., 2008; Stranges et al., 2007). Apoptosis is facilitated by the AICD mechanism triggered predominantly by Fas-L which itself is induced by ROS (Stranges et al., 2007). Activation caused autonomous death (ACAD) also mediates apoptosis (Hildeman et al., 1999) but this is via pro- and anti-apoptotic members of Bcl-2 family proteins (Hildeman et al., 2003b). The ROS driven apoptosis serves to regulate the number of activated T cells. Interestingly, ROS have been implicated in down regulation of Bcl-2 in activated T cells (Hildeman et al., 2003a). Additionally, the increase in mitochondrial content during early activation could contribute to apoptosis through cytochrome c release via Ca21 and ROS-dependent mitochondrial permeability transition pore opening (Crompton, 1999). Thus, alteration in the status of mitochondria and ROS could transform the activation, kinetics and population of activated T cell and thereby modulate T cell homeostasis to regulate the adaptive immune response. This chapter will focus on the sources and targets of ROS, specifically on the oxidants of mitochondrial origin and the mechanisms of oxidant-induced effects on T cell activation.
Immunity and Inflammation in Health and Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-805417-8.00005-6
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Copyright © 2018 Elsevier Inc. All rights reserved.
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5.2. REACTIVE OXYGEN SPECIES ROS are small short-lived molecules derived from oxygen (O2) that are chemically highly reactive and readily oxidize other molecules in vicinity. The extreme reactivity is contributed by the unpaired electrons (radicals). Hydrogen peroxide (H2O2), superoxide (O22 ), hydroxyl radical (OH ), hypochlorous acid (HOCl), lipid peroxides (ROOH), singlet oxygen (1O2), and ozone (O3) are the common forms of ROS (Winterbourn, 2008). Superoxide and hydrogen peroxide are the most important forms of ROS involved in the regulation of many biological processes. Most of the forms of intracellular ROS are derived primarily from O22 . O22 once produced, rapidly react with surrounding molecules or get converted to H2O2 by superoxide dismutases (SODs) (Miller, 2012). Compared to O22 , H2O2 is more stable, less reactive, can diffuse rapidly in the cellular microenvironment, and has the ability to cross cell membranes. ROS are of exogenous or endogenous origin; exogenous sources of ROS, includes ultraviolet and gamma radiation, air pollutants such as smoke, chemicals such as hydrogen peroxide as well as several drugs. Endogenous sources of ROS are generated from enzymes often compartmentalized in mitochondria, plasma membrane, phagosomes, endoplasmic reticulum, peroxisomes, and cytosol. Among these regulatory ROS generators -NADPH oxidases or NOX enzymes and the mitochondrial ROS are the major contributors of cellular superoxide and hydrogen peroxide. NOX-derived ROS is mostly involved in ROS-dependent pathogen killing and is expressed highly in phagocytic cells such as macrophages, neutrophils and dendritic cells, and in low levels in B cells, NK cells, mast cells and eosinophils (Babior, 1984). In these cell types, ROS are produced by the phagocytic NADPH oxidase (PHOX), an enzyme consisting of several subunits (Quinn and Gauss, 2004). NOX-2 (gp91phox) the extensively studied isoform, and is expressed at either the plasma or phagosomes’ membrane. Interestingly, six homologs of gp91phox (NOX-2) have been identified in different tissues: NOX-1, NOX-3, NOX-4, NOX-5, dual oxidase 1 (DUOX-1), and DUOX-2 (Lambeth, 2004; Bedard and Krause, 2007). Activation of cellular receptors by several ligands such as tumor necrosis factor (TNF-α), platelet derived growth factor (PDGF), granulocyte macrophage colony stimulating factor (GM-CSF), angiotensin, insulin, chemokines that bind G protein-coupled receptors, complement component 5a (C5a), lysophospholipids, and leukotriene B4, as well as by cell adhesion triggers the NOX production (Nathan and Cunningham-Bussel, 2013). Because of the widespread expression of NOX and DUOX isoforms across organelles, different cell types, and organisms, NOX enzymes have traditionally been considered to be the major sources of ROS that drive myriad cellular signaling (Brown and Griendling, 2009). However, work over the past decade or more shows that ROS produced by the mitochondrial electron transport chain (ETC) or mitochondrial metabolic enzymes also mediates a wide range of signal transduction (Hamanaka and Chandel, 2010; Sandalio et al., 2013). It has to be noted that the physiological low levels of mitochondrial ROS are important for signal transduction and are much different from that of the signaling cascades activated during oxidative stress. Since the specificity and functional role of mROS is dependent on its levels, stringent regulation of mROS is crucial for its proper function in cellular signaling. The physiological low levels of mitochondrial ROS are kept in balance by antioxidant systems in the cell.
5.3. SOURCES OF MITOCHONDRIAL ROS Mitochondria form the major source of endogenous ROS and a significant amount of mitochondria ROS (mROS) is generated by its aerobic respiration (Kowaltowski et al., 2009; Finkel, 2011, 2012). Mitochondrial inner membrane harbors the respiratory chain complexes, which transfer electrons (received from reducing equivalents coming of the Krebs cycle such as NADH and succinate), across the complexes to the final electron acceptor, the molecular oxygen (O2). O2 is reduced to H2O upon receiving four electrons from the electron transport chain (ETC). Nonetheless, the respiratory chain is not perfectly ideal, and sometimes electron slippage occurs from the ETC, reduces the molecular O2 that is readily available in the vicinity and reduces to superoxide (O2 2 ) or Hydrogen peroxide (H2O2). Traditionally, Complex I (NADH dehydrogenase) and complex III (ubiquinone-cytochrome c reductase) are the major sites for mitochondrial O2 2 production that carries out various cellular signaling functions (Drose and Brandt, 2012; Lambert and Brand, 2009). In recent years many other sources of mitochondrial ROS have been identified making a total of 11 different sources of mROS (Mailloux, 2015). Each source of mROS has a different redox potential at which ROS is produced. Based on this, Brand and colleagues recently suggested a classification of mROS producing enzymes broadly into two different isopotential subgroups namely (1) NADH/NAD isopotential group and (2) QH2/Q isopotential group (Quinlan et al., 2013, 2014).
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The NADH/NAD isopotential group consists of four enzymes: Complex I (NADH dehydrogenase), 2-oxoglutarate dehydrogenase (Odh), Pyruvate dehydrogenase (PDH), and Branched-chain oxo-acid dehydrogenase phosphatase (Bckdh). The QH2/Q isopotential group is made up of seven enzymes; Complex III (ubiquinonecytochrome c reductase), Succinate dehydrogenase (Complex II), Electron-transfer flavoprotein:ubiquinone oxidoreductase (ETFQO), proline dehydrogenase, dihydroorotate dehydrogenase, Succinate-coenzyme Q reductase (SQR), and sn-glycerol-3-phosphate dehydrogenase (sn-G3PDH). The ROS production in the NADH/NAD isopotential group is dependent on the concentration of NADH, whereas in the QH2/Q isopotential group it is subject to reduction of Q to QH2. Notably, in the QH2/Q group the major sources of ROS are attributed to reverse electron transport (RET) as they arise from Complex II, and III (Quinlan et al., 2013, 2014; Goncalves et al., 2014).
5.4. REGULATION OF mROS Prolonged or excessive ROS production can lead to the impairment of cellular functions, cell death, senescence, or malignant transformation (Mailloux, 2015; Finkel and Holbrook, 2000; Reuter et al., 2010). The rates of mROS production from the different enzymatic sources are highly dependent on nutrient availability, mitochondrial redox status, and availability of ADP. Since the magnitude of mROS dictates its specificity and functional consequences, strict regulatory mechanisms are essential to harness and employ in specific cellular signaling. Thus the mROS signaling is controlled by several regulatory mechanisms. Antioxidants form the first and foremost regulatory component in mROS regulation. While low levels of ROS are of physiologic significance, excessive mROS could potentially cause damaging effects. In order to avoid the damages caused by excess ROS, mitochondria harbor a number of antioxidants. Dismutases such as SOD2, which rapidly and spontaneously dismutate superoxide to hydrogen peroxide, form the major pool of antioxidants. Other scavenging enzymes such as peroxiredoxins (PRX) undergo oxidation in the presence of H2O2 at an active cysteine site and then subsequently reduced by thioredoxin, thioredoxin reductase and NADPH. Of the six mammalian peroxiredoxin isoforms, PRX 3 and 5 are expressed in mitochondria. Although the activities of intracellular antioxidants and ROS scavengers determine the ROS levels, the magnitude of mROS generated also rely on mitochondrial bioenergetics. Specifically, mitochondrial membrane potential could modulate the ROS production wherein the increased membrane potential (Δψm) is believed to favor the production of ROS, whereas mitochondrial uncoupling agents that dissipate Δψm lower the mROS production. Furthermore, defects in components of the ETC that lead to disruption of electron flow could also modulate the ROS production. In addition, most of these enzymes that participate in ROS production have thiol residues that are close to or adjacent to ROS producing centers which indicates that the redox signaling may mechanistically control the ROS production (Mailloux et al., 2014). For instance, 2-oxoglutarate dehydrogenase produces both superoxide and hydrogen peroxide at the same time and these ROS deactivate the enzyme and thus ROS production by a negative feedback mechanism (Tretter and Adam-Vizi, 1999; Starkov et al., 2004). Other factors such as mitochondrial fission and fusion and assembly of Krebs cycle enzymes and respiratory complexes also could influence ROS production (Yu et al., 2006; Winge, 2012).
5.5. TARGETS OF mROS ROS can interact with a wide range of macromolecules and modulate its function. Increasing evidence suggests that ROS can cause reversible post-translational modifications in mitochondrial proteins and thereby regulates many signaling pathways. H2O2 is a highly stable ROS and acts as the major signaling messenger that has the ability to traverse across cellular or organelle membranes (Quinlan et al., 2012). H2O2 reacts preferentially with thiol groups ( SH) on cysteine residues to form sulphenic acid by a process called sulfenylation (Ilbert and Bonnefoy, 2013). Sulfenylation may lead to further post-translational modifications, such as glutathionylation when sulphenic acid reacts with GSH, disulfide bond formation when sulphenic acid reacts with adjacent thiols, and sulfinilation when sulphenic acid reacts with amides to form sulphenyl amides (Lagoutte et al., 2010; Watt et al., 2010). Sulfenylation and the subsequent modifications can bring changes in the protein conformation, either leading to the activation or inactivation of the catalytic center or confer other functional alterations of the sulfenylated protein, thus altering its role in the signaling pathway. Interestingly, sulfenylation could be reversed by glutothioredoxins and thioredoxins (Shabalina et al., 2014; Harel et al., 2014). Multiple classes of proteins have been
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shown to be regulated by sulfenylation, including phosphatases and kinases (such as PTP1b, PTEN, and MAPK), transcription factors and histone deacetylases, antioxidant enzymes and heat-shock proteins, proteases and hydrolases, ion channels and pumps, adaptor molecules and cytoskeleton components (Goncalves et al., 2014; Lagoutte et al., 2010; Watt et al., 2010; Lane, 2014).
5.6. MITOCHONDRIAL ROS IN T CELL ACTIVATION Mitochondrial ROS are gradually gaining recognition as important signaling mediators in wide range of cellular processes, such as metabolic adaptation, adaptive responses to hypoxia, cellular differentiation, autophagy and regulation of innate or adaptive immunity (Finkel, 2012; Sena and Chandel, 2012). More recently, the importance of mitochondria and mitochondrial-derived free radicals in T cell physiology is being recognized. Mitochondrial metabolism plays a crucial role in determining the fate of T cell differentiation into memory and regulatory phenotypes (Gerriets and Rathmell, 2012; Wang and Green, 2012). Several studies in the last decade have implicated the importance of mitochondria in the immunological synapse, where mitochondria centrally act as calcium buffers, thus determining the amplitude and duration of Ca21 signals and also provide a strong ATP gradient for TCR-mediated phosphorylation events (Hoth et al., 1997; Baixauli et al., 2011; Quintana et al., 2006, 2007). This buffering of Ca21 occurs through the uniporter channel and is dependent on intact mitochondrial membrane potential (Mallilankaraman et al., 2012a,b). Hence a defect in mitochondrial membrane potential either due to mtDNA depletion or mitochondrial uncoupling will result in dampened TCR-induced Ca21 signal due to a reduction in the ability to buffer and prolong Ca21 influx (Hoth et al., 2000; Koziel et al., 2006). T cell activation-induced mitochondrial Ca21 uptake is also known to stimulate mitochondrial function by activating the Ca21 dependent enzymes of the TCA (tri-carboxylic acid) cycle (Carafoli, 2012). The initial phase of T cell activation triggers the proliferation of naive T cells. This process is associated with an increase in mitochondrial DNA (mtDNA) content, mitochondrial mass and oxidative phosphorylation (OXPHOS) activity (D’Souza et al., 2007; Darzynkiewicz et al., 1981; Frauwirth and Thompson, 2004). The rapid increase in OXPHOS activity leads to increased mROS production, which in turn drives T cell activation-induced ROS production (Kaminski et al., 2007, 2010; Yi et al., 2006; Nagy et al., 2003). The receptor on T cells, the TCR and the costimulatory molecule CD28, when activated, lead to mitochondrial hyperpolarization as well as ROS overproduction. T cell activation-induced mROS production induces chemokines, CD95L and antioxidant genes via the activation of transcription factors NF-κB- and AP-1 (Nagy et al., 2003). Furthermore, TCR -induced mROS is known to participate in AICD and ACAD. The requirement of intact mitochondria for T cell activation-induced ROS production was revealed using mtDNA-depleted Jurkat T cells (ps-ρ0 phenotype), and in mtDNA-depleted human T cells (by prolonged ciprofloxacin exposure) (Kaminski et al., 2007, 2010). Cells devoid of mtDNA showed diminished levels of activation-induced ROS, which resulted in decreased expression of IL-2, IL-4 and CD95L. In addition the mtDNA-less cells were protected from CD95L-dependent AICD. Several in vitro studies have implicated the requirement of mROS for T cell activation and subsequent proliferation and clonal expansion; however these findings have not been confirmed in in vivo model systems. Although there are 11 known sources of mROS, Complex I and III seem to be the main sources that contribute in T cell activation and associated signaling. Complex I releases ROS towards the matrix while the Complex III releases ROS towards the intermembranous spaces. Several studies have shown that inhibition of Complex I (with rotenone, a potent inhibitor of complex I) blocks T cell activation-induced mROS production (Kaminski et al., 2007, 2010, 2012; Yi et al., 2006) and subsequent IL-2, IL-4 and CD95L gene expression (Kaminski et al., 2007, 2010; Bauer et al., 1998). Because rotenone also interferes with centrosomal function and tubulin assembly (Brinkley et al., 1974; Diaz-Corrales et al., 2005), other inhibitors of Complex I (piericidin A and metformin (an anti-diabetic and mild complex I blocker)) have also been used and these too conformed the role of ROS released via Complex I in T cell activation (El-Mir et al., 2000; Horgan et al., 1968). Studies were also carried out using knock-down of an essential complex I assembly factor NDUFAF1 (Vogel et al., 2005). These revealed that NDUFAF1 abrogated T-cell activation-induced ROS generation. Superoxide generated at Complex I is converted into H2O2 by matrix localized SODs (MnSOD, SOD2) (Kaminski et al., 2007, 2010). H2O2 can cross mitochondrial membranes and diffuse into the cytoplasm to participate in oxidative signal transduction. T Cell activation leads to an increased superoxide levels in the mitochondrial matrix (Kaminski et al., 2012; Sena and Chandel, 2012). The increased superoxide could potentially trigger MnSOD, a major matrix antioxidant (Kaminski et al., 2012;
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Kiessling et al., 2010). Interestingly, MnSOD content and activity was shown to be upregulated with T cell activation. MnSOD, upregulated during the late phase of a TCR-induced response, is considered a critical regulator of oxidative signal generation (Kaminski et al., 2012). Thus, intact, functional respiratory complex I is indispensable for the mitochondrial ROS production during T cell activation. Intact respiratory complex III is shown to be required for antigen-specific (TCR- and CD28-mediated) T cell activation-induced mitochondrial ROS generation. T cell specific conditional knockout of complex III subunit RISP, showed impairment in CD41 and CD81 T-cell responses. In this study it was suggested that complex IIIderived mitochondrial ROS release to be dependent on Tcell activation-induced mitochondrial Ca21 uptake and up-regulation of the Krebs cycle. Further, the complex III-derived ROS was suggested to enhance the activation of NFAT and Ca21-dependent transcription. Thus complex III mediated mROS production is crucial for T-cell activation (Kaminski et al., 2012; Sena and Chandel, 2012). Inhibition of both Complex III (inhibitor: antimycin A) and Complex IV (inhibitor: NaN3) potentiates TCR-induced mROS production. T cell activation is followed by a metabolic switch from mitochondrial ATP dependent to aerobic glycolysis similar to that of the Warburg effect observed in cancer cells (Wang et al., 1976; Warburg, 1956; Vander Heiden et al., 2009). Glucose influx is critical for the glycolytic phase of the activation process to potentiate TCR-triggered transcription (Jacobs et al., 2008; Stentz and Kitabchi, 2005). Interestingly, in in vitro expanded human T cells, TCRinduced mROS production is complemented by a metabolic switch closely resembling the Warburg effect. Glucose uptake and cellular ATP concentration rise while mitochondrial respiration coupled ATP production declines. Mitochondria display cristae rearrangements closely reminiscent of ROS release and low respiratory activity (Arismendi-Morillo, 2011). This immediate metabolic change and redirection of glycolytic flow due to the induction of ATP-independent phospho-enol pyruvate phosphatase activity leads to activation of the mitochondrial glycerol3-phosphate shuttle via the inner membrane localized GPD2 (glycerol-3-phosphate dehydrogenase 2) (Kaminski et al., 2012; Vander Heiden et al., 2009). GPD2 knock-down abrogates the mROS production, NF-κB activation and the downstream NF-κB-dependent transcription (Kaminski et al., 2012; Vander Heiden et al., 2009). This suggests that the metabolic switch from mitochondrial respiration to aerobic glycolysis mediates mitochondrial ROS production. Activated GPD2 is shown to directly reduce ubiquinone and release mROS via complex I. Thus, GPD2 acts as a major player in T cell activation-induced ROS release during the metabolic switch. In addition to GPD2, TCR-triggered metabolic switch also activates another glycolytic enzyme, ADPGK (ADPdependent glucokinase). The PKC-dependent ADPGK activity is triggered shortly after TCR-mediated stimulation. Modulating the ADPGK levels by either knock-down or over-expression reveal the crucial role of ADPGK in activation-induced ROS production. Although ADPGK is an ER resident protein with its active site exposed on the cytosolic side, its activation could enhance the glycolytic flux and thus possibly contribute to mROS production (Kaminski et al., 2012; Vander Heiden et al., 2009).
5.7. SUMMARY ROS are well established to play a crucial role in cellular signal transduction and mitochondria as a source of endogenous ROS, are increasingly being evaluated. There are 11 different sites within mitochondria that act as centers of ROS production but till date our knowledge on ROS, T cell activation and T cell induced mROS production is limited to Complex I and III and to some extent complex IV. ROS is regulated tightly by antioxidant mechanisms within mitochondria that comprise antioxidant enzymes and ROS scavengers. There is growing interest in antioxidant-mediated mROS regulation in T cell activation process. Most of the studies are focused on SODs that reside within mitochondrial matrix. While the involvement of respiratory complexes in mROS production is convincing, one should remember all these studies are limited to in vitro conditions. Among the varied reasons for this limitation is the lack of highly sensitive experimental techniques that could measure compartmentalized ROS in a spatiotemporal manner. Further, the lack of knockout mouse models where mitochondrial ROS is compromised is another major limitation. This is because the respiratory complexes are indispensable in mice. Despite these limitations, new evidence of the crucial role of mitochondrial oxidants in T cell activation process is gradually emerging. Functional respiratory complex I (and complex III), and MnSOD activity as well as the metabolic switch from mitochondrial ATP to aerobic glycolysis triggering the GDP2 and ADPGK constitute the crucial players in T cell activation process. Nevertheless, more research is needed to further understand the in vivo molecular mechanisms of T cell activation-induced mitochondrial ROS production.
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5 Mitochondrial ROS and T Cell Activation Karthik B. Mallilankaraman National University of Singapore, Singapore, Singapore
5.1. INTRODUCTION Stimulation of the T cell receptor (TCR) by foreign antigens through antigen-presenting cells (APCs) drives the T cells into rapid proliferation and differentiation, wherein naive T cells expand clonally and differentiate to become effector T cells. Traditionally, TCR stimulation results in PLC-γ1 induction that causes T cells to proliferate and differentiate via Inositol 3,4,5-triphosphate (IP3) mediated rise in cytosolic Ca21 and downstream activation of Ca21-dependent transcription factors. These transcription factors are nuclear factors of activated T cells (NFAT), NF-κB and AP-1 and are well established to control the T cell activation-induced gene expression. While NFAT is predominantly Ca21 dependent, NF-κB and AP-1 are promiscuous and can be activated by low physiological levels of reactive oxygen species (ROS) that is generated transiently during the T cell activation process (Droge, 2002; Kaminski et al., 2010, 2012) Thus, oxidative signal can be considered to be indispensable for T cell activation (Droge, 2002; Kaminski et al., 2010; Devadas et al., 2002). Together with the Ca21 influx, low levels of ROS constitutes the nominal requirement for activation-induced expression of genes such as interleukin 2 (IL-2), a major autocrine factor for T cell proliferation (Meuer et al., 1984), IL-4 and CD95L (Kaminski et al., 2007, 2010; Devadas et al., 2002; Gulow et al., 2005). During T cell activation, ROS is produced from different sources such as NADPH oxidases (NOX2, DUOX2), lipoxygenases (Jackson et al., 2004; Kwon et al., 2010; Los et al., 1995), and the mitochondrial respiratory chain (Kaminski et al., 2007, 2010, 2012; Yi et al., 2006). T cell activation is a highly energy demanding process, where mitochondrial ATP production plays a pivotal role. To meet the high energy demand during the activation process, T cells increase their mitochondrial biogenesis and respiratory chain activity (D’Souza et al., 2007). Increased mitochondrial respiration results in the rapid increase in mitochondrial ROS (Grayson et al., 2003). Activation of T cells is immediately followed by clonal expansion through rapid proliferation and differentiation. While physiological levels of ROS play an important role in T cell activation, uncontrolled high-levels of ROS affect the clonal expansion and result in removal of activated cells (Hildeman et al., 1999). A fine balance between these two events of activation and expansion requires optimal levels of ROS. ROS also drives apoptosis in activated T cells either via activation-induced cell death (AICD) or activated cell autonomous death (ACAD) (Meuer et al., 1984; D’Souza et al., 2007; Hildeman et al., 1999; Brenner et al., 2008; Stranges et al., 2007). Apoptosis is facilitated by the AICD mechanism triggered predominantly by Fas-L which itself is induced by ROS (Stranges et al., 2007). Activation caused autonomous death (ACAD) also mediates apoptosis (Hildeman et al., 1999) but this is via pro- and anti-apoptotic members of Bcl-2 family proteins (Hildeman et al., 2003b). The ROS driven apoptosis serves to regulate the number of activated T cells. Interestingly, ROS have been implicated in down regulation of Bcl-2 in activated T cells (Hildeman et al., 2003a). Additionally, the increase in mitochondrial content during early activation could contribute to apoptosis through cytochrome c release via Ca21 and ROS-dependent mitochondrial permeability transition pore opening (Crompton, 1999). Thus, alteration in the status of mitochondria and ROS could transform the activation, kinetics and population of activated T cell and thereby modulate T cell homeostasis to regulate the adaptive immune response. This chapter will focus on the sources and targets of ROS, specifically on the oxidants of mitochondrial origin and the mechanisms of oxidant-induced effects on T cell activation.
Immunity and Inflammation in Health and Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-805417-8.00005-6
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5.2. REACTIVE OXYGEN SPECIES ROS are small short-lived molecules derived from oxygen (O2) that are chemically highly reactive and readily oxidize other molecules in vicinity. The extreme reactivity is contributed by the unpaired electrons (radicals). Hydrogen peroxide (H2O2), superoxide (O22 ), hydroxyl radical (OH ), hypochlorous acid (HOCl), lipid peroxides (ROOH), singlet oxygen (1O2), and ozone (O3) are the common forms of ROS (Winterbourn, 2008). Superoxide and hydrogen peroxide are the most important forms of ROS involved in the regulation of many biological processes. Most of the forms of intracellular ROS are derived primarily from O22 . O22 once produced, rapidly react with surrounding molecules or get converted to H2O2 by superoxide dismutases (SODs) (Miller, 2012). Compared to O22 , H2O2 is more stable, less reactive, can diffuse rapidly in the cellular microenvironment, and has the ability to cross cell membranes. ROS are of exogenous or endogenous origin; exogenous sources of ROS, includes ultraviolet and gamma radiation, air pollutants such as smoke, chemicals such as hydrogen peroxide as well as several drugs. Endogenous sources of ROS are generated from enzymes often compartmentalized in mitochondria, plasma membrane, phagosomes, endoplasmic reticulum, peroxisomes, and cytosol. Among these regulatory ROS generators -NADPH oxidases or NOX enzymes and the mitochondrial ROS are the major contributors of cellular superoxide and hydrogen peroxide. NOX-derived ROS is mostly involved in ROS-dependent pathogen killing and is expressed highly in phagocytic cells such as macrophages, neutrophils and dendritic cells, and in low levels in B cells, NK cells, mast cells and eosinophils (Babior, 1984). In these cell types, ROS are produced by the phagocytic NADPH oxidase (PHOX), an enzyme consisting of several subunits (Quinn and Gauss, 2004). NOX-2 (gp91phox) the extensively studied isoform, and is expressed at either the plasma or phagosomes’ membrane. Interestingly, six homologs of gp91phox (NOX-2) have been identified in different tissues: NOX-1, NOX-3, NOX-4, NOX-5, dual oxidase 1 (DUOX-1), and DUOX-2 (Lambeth, 2004; Bedard and Krause, 2007). Activation of cellular receptors by several ligands such as tumor necrosis factor (TNF-α), platelet derived growth factor (PDGF), granulocyte macrophage colony stimulating factor (GM-CSF), angiotensin, insulin, chemokines that bind G protein-coupled receptors, complement component 5a (C5a), lysophospholipids, and leukotriene B4, as well as by cell adhesion triggers the NOX production (Nathan and Cunningham-Bussel, 2013). Because of the widespread expression of NOX and DUOX isoforms across organelles, different cell types, and organisms, NOX enzymes have traditionally been considered to be the major sources of ROS that drive myriad cellular signaling (Brown and Griendling, 2009). However, work over the past decade or more shows that ROS produced by the mitochondrial electron transport chain (ETC) or mitochondrial metabolic enzymes also mediates a wide range of signal transduction (Hamanaka and Chandel, 2010; Sandalio et al., 2013). It has to be noted that the physiological low levels of mitochondrial ROS are important for signal transduction and are much different from that of the signaling cascades activated during oxidative stress. Since the specificity and functional role of mROS is dependent on its levels, stringent regulation of mROS is crucial for its proper function in cellular signaling. The physiological low levels of mitochondrial ROS are kept in balance by antioxidant systems in the cell.
5.3. SOURCES OF MITOCHONDRIAL ROS Mitochondria form the major source of endogenous ROS and a significant amount of mitochondria ROS (mROS) is generated by its aerobic respiration (Kowaltowski et al., 2009; Finkel, 2011, 2012). Mitochondrial inner membrane harbors the respiratory chain complexes, which transfer electrons (received from reducing equivalents coming of the Krebs cycle such as NADH and succinate), across the complexes to the final electron acceptor, the molecular oxygen (O2). O2 is reduced to H2O upon receiving four electrons from the electron transport chain (ETC). Nonetheless, the respiratory chain is not perfectly ideal, and sometimes electron slippage occurs from the ETC, reduces the molecular O2 that is readily available in the vicinity and reduces to superoxide (O2 2 ) or Hydrogen peroxide (H2O2). Traditionally, Complex I (NADH dehydrogenase) and complex III (ubiquinone-cytochrome c reductase) are the major sites for mitochondrial O2 2 production that carries out various cellular signaling functions (Drose and Brandt, 2012; Lambert and Brand, 2009). In recent years many other sources of mitochondrial ROS have been identified making a total of 11 different sources of mROS (Mailloux, 2015). Each source of mROS has a different redox potential at which ROS is produced. Based on this, Brand and colleagues recently suggested a classification of mROS producing enzymes broadly into two different isopotential subgroups namely (1) NADH/NAD isopotential group and (2) QH2/Q isopotential group (Quinlan et al., 2013, 2014).
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The NADH/NAD isopotential group consists of four enzymes: Complex I (NADH dehydrogenase), 2-oxoglutarate dehydrogenase (Odh), Pyruvate dehydrogenase (PDH), and Branched-chain oxo-acid dehydrogenase phosphatase (Bckdh). The QH2/Q isopotential group is made up of seven enzymes; Complex III (ubiquinonecytochrome c reductase), Succinate dehydrogenase (Complex II), Electron-transfer flavoprotein:ubiquinone oxidoreductase (ETFQO), proline dehydrogenase, dihydroorotate dehydrogenase, Succinate-coenzyme Q reductase (SQR), and sn-glycerol-3-phosphate dehydrogenase (sn-G3PDH). The ROS production in the NADH/NAD isopotential group is dependent on the concentration of NADH, whereas in the QH2/Q isopotential group it is subject to reduction of Q to QH2. Notably, in the QH2/Q group the major sources of ROS are attributed to reverse electron transport (RET) as they arise from Complex II, and III (Quinlan et al., 2013, 2014; Goncalves et al., 2014).
5.4. REGULATION OF mROS Prolonged or excessive ROS production can lead to the impairment of cellular functions, cell death, senescence, or malignant transformation (Mailloux, 2015; Finkel and Holbrook, 2000; Reuter et al., 2010). The rates of mROS production from the different enzymatic sources are highly dependent on nutrient availability, mitochondrial redox status, and availability of ADP. Since the magnitude of mROS dictates its specificity and functional consequences, strict regulatory mechanisms are essential to harness and employ in specific cellular signaling. Thus the mROS signaling is controlled by several regulatory mechanisms. Antioxidants form the first and foremost regulatory component in mROS regulation. While low levels of ROS are of physiologic significance, excessive mROS could potentially cause damaging effects. In order to avoid the damages caused by excess ROS, mitochondria harbor a number of antioxidants. Dismutases such as SOD2, which rapidly and spontaneously dismutate superoxide to hydrogen peroxide, form the major pool of antioxidants. Other scavenging enzymes such as peroxiredoxins (PRX) undergo oxidation in the presence of H2O2 at an active cysteine site and then subsequently reduced by thioredoxin, thioredoxin reductase and NADPH. Of the six mammalian peroxiredoxin isoforms, PRX 3 and 5 are expressed in mitochondria. Although the activities of intracellular antioxidants and ROS scavengers determine the ROS levels, the magnitude of mROS generated also rely on mitochondrial bioenergetics. Specifically, mitochondrial membrane potential could modulate the ROS production wherein the increased membrane potential (Δψm) is believed to favor the production of ROS, whereas mitochondrial uncoupling agents that dissipate Δψm lower the mROS production. Furthermore, defects in components of the ETC that lead to disruption of electron flow could also modulate the ROS production. In addition, most of these enzymes that participate in ROS production have thiol residues that are close to or adjacent to ROS producing centers which indicates that the redox signaling may mechanistically control the ROS production (Mailloux et al., 2014). For instance, 2-oxoglutarate dehydrogenase produces both superoxide and hydrogen peroxide at the same time and these ROS deactivate the enzyme and thus ROS production by a negative feedback mechanism (Tretter and Adam-Vizi, 1999; Starkov et al., 2004). Other factors such as mitochondrial fission and fusion and assembly of Krebs cycle enzymes and respiratory complexes also could influence ROS production (Yu et al., 2006; Winge, 2012).
5.5. TARGETS OF mROS ROS can interact with a wide range of macromolecules and modulate its function. Increasing evidence suggests that ROS can cause reversible post-translational modifications in mitochondrial proteins and thereby regulates many signaling pathways. H2O2 is a highly stable ROS and acts as the major signaling messenger that has the ability to traverse across cellular or organelle membranes (Quinlan et al., 2012). H2O2 reacts preferentially with thiol groups ( SH) on cysteine residues to form sulphenic acid by a process called sulfenylation (Ilbert and Bonnefoy, 2013). Sulfenylation may lead to further post-translational modifications, such as glutathionylation when sulphenic acid reacts with GSH, disulfide bond formation when sulphenic acid reacts with adjacent thiols, and sulfinilation when sulphenic acid reacts with amides to form sulphenyl amides (Lagoutte et al., 2010; Watt et al., 2010). Sulfenylation and the subsequent modifications can bring changes in the protein conformation, either leading to the activation or inactivation of the catalytic center or confer other functional alterations of the sulfenylated protein, thus altering its role in the signaling pathway. Interestingly, sulfenylation could be reversed by glutothioredoxins and thioredoxins (Shabalina et al., 2014; Harel et al., 2014). Multiple classes of proteins have been
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shown to be regulated by sulfenylation, including phosphatases and kinases (such as PTP1b, PTEN, and MAPK), transcription factors and histone deacetylases, antioxidant enzymes and heat-shock proteins, proteases and hydrolases, ion channels and pumps, adaptor molecules and cytoskeleton components (Goncalves et al., 2014; Lagoutte et al., 2010; Watt et al., 2010; Lane, 2014).
5.6. MITOCHONDRIAL ROS IN T CELL ACTIVATION Mitochondrial ROS are gradually gaining recognition as important signaling mediators in wide range of cellular processes, such as metabolic adaptation, adaptive responses to hypoxia, cellular differentiation, autophagy and regulation of innate or adaptive immunity (Finkel, 2012; Sena and Chandel, 2012). More recently, the importance of mitochondria and mitochondrial-derived free radicals in T cell physiology is being recognized. Mitochondrial metabolism plays a crucial role in determining the fate of T cell differentiation into memory and regulatory phenotypes (Gerriets and Rathmell, 2012; Wang and Green, 2012). Several studies in the last decade have implicated the importance of mitochondria in the immunological synapse, where mitochondria centrally act as calcium buffers, thus determining the amplitude and duration of Ca21 signals and also provide a strong ATP gradient for TCR-mediated phosphorylation events (Hoth et al., 1997; Baixauli et al., 2011; Quintana et al., 2006, 2007). This buffering of Ca21 occurs through the uniporter channel and is dependent on intact mitochondrial membrane potential (Mallilankaraman et al., 2012a,b). Hence a defect in mitochondrial membrane potential either due to mtDNA depletion or mitochondrial uncoupling will result in dampened TCR-induced Ca21 signal due to a reduction in the ability to buffer and prolong Ca21 influx (Hoth et al., 2000; Koziel et al., 2006). T cell activation-induced mitochondrial Ca21 uptake is also known to stimulate mitochondrial function by activating the Ca21 dependent enzymes of the TCA (tri-carboxylic acid) cycle (Carafoli, 2012). The initial phase of T cell activation triggers the proliferation of naive T cells. This process is associated with an increase in mitochondrial DNA (mtDNA) content, mitochondrial mass and oxidative phosphorylation (OXPHOS) activity (D’Souza et al., 2007; Darzynkiewicz et al., 1981; Frauwirth and Thompson, 2004). The rapid increase in OXPHOS activity leads to increased mROS production, which in turn drives T cell activation-induced ROS production (Kaminski et al., 2007, 2010; Yi et al., 2006; Nagy et al., 2003). The receptor on T cells, the TCR and the costimulatory molecule CD28, when activated, lead to mitochondrial hyperpolarization as well as ROS overproduction. T cell activation-induced mROS production induces chemokines, CD95L and antioxidant genes via the activation of transcription factors NF-κB- and AP-1 (Nagy et al., 2003). Furthermore, TCR -induced mROS is known to participate in AICD and ACAD. The requirement of intact mitochondria for T cell activation-induced ROS production was revealed using mtDNA-depleted Jurkat T cells (ps-ρ0 phenotype), and in mtDNA-depleted human T cells (by prolonged ciprofloxacin exposure) (Kaminski et al., 2007, 2010). Cells devoid of mtDNA showed diminished levels of activation-induced ROS, which resulted in decreased expression of IL-2, IL-4 and CD95L. In addition the mtDNA-less cells were protected from CD95L-dependent AICD. Several in vitro studies have implicated the requirement of mROS for T cell activation and subsequent proliferation and clonal expansion; however these findings have not been confirmed in in vivo model systems. Although there are 11 known sources of mROS, Complex I and III seem to be the main sources that contribute in T cell activation and associated signaling. Complex I releases ROS towards the matrix while the Complex III releases ROS towards the intermembranous spaces. Several studies have shown that inhibition of Complex I (with rotenone, a potent inhibitor of complex I) blocks T cell activation-induced mROS production (Kaminski et al., 2007, 2010, 2012; Yi et al., 2006) and subsequent IL-2, IL-4 and CD95L gene expression (Kaminski et al., 2007, 2010; Bauer et al., 1998). Because rotenone also interferes with centrosomal function and tubulin assembly (Brinkley et al., 1974; Diaz-Corrales et al., 2005), other inhibitors of Complex I (piericidin A and metformin (an anti-diabetic and mild complex I blocker)) have also been used and these too conformed the role of ROS released via Complex I in T cell activation (El-Mir et al., 2000; Horgan et al., 1968). Studies were also carried out using knock-down of an essential complex I assembly factor NDUFAF1 (Vogel et al., 2005). These revealed that NDUFAF1 abrogated T-cell activation-induced ROS generation. Superoxide generated at Complex I is converted into H2O2 by matrix localized SODs (MnSOD, SOD2) (Kaminski et al., 2007, 2010). H2O2 can cross mitochondrial membranes and diffuse into the cytoplasm to participate in oxidative signal transduction. T Cell activation leads to an increased superoxide levels in the mitochondrial matrix (Kaminski et al., 2012; Sena and Chandel, 2012). The increased superoxide could potentially trigger MnSOD, a major matrix antioxidant (Kaminski et al., 2012;
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Kiessling et al., 2010). Interestingly, MnSOD content and activity was shown to be upregulated with T cell activation. MnSOD, upregulated during the late phase of a TCR-induced response, is considered a critical regulator of oxidative signal generation (Kaminski et al., 2012). Thus, intact, functional respiratory complex I is indispensable for the mitochondrial ROS production during T cell activation. Intact respiratory complex III is shown to be required for antigen-specific (TCR- and CD28-mediated) T cell activation-induced mitochondrial ROS generation. T cell specific conditional knockout of complex III subunit RISP, showed impairment in CD41 and CD81 T-cell responses. In this study it was suggested that complex IIIderived mitochondrial ROS release to be dependent on Tcell activation-induced mitochondrial Ca21 uptake and up-regulation of the Krebs cycle. Further, the complex III-derived ROS was suggested to enhance the activation of NFAT and Ca21-dependent transcription. Thus complex III mediated mROS production is crucial for T-cell activation (Kaminski et al., 2012; Sena and Chandel, 2012). Inhibition of both Complex III (inhibitor: antimycin A) and Complex IV (inhibitor: NaN3) potentiates TCR-induced mROS production. T cell activation is followed by a metabolic switch from mitochondrial ATP dependent to aerobic glycolysis similar to that of the Warburg effect observed in cancer cells (Wang et al., 1976; Warburg, 1956; Vander Heiden et al., 2009). Glucose influx is critical for the glycolytic phase of the activation process to potentiate TCR-triggered transcription (Jacobs et al., 2008; Stentz and Kitabchi, 2005). Interestingly, in in vitro expanded human T cells, TCRinduced mROS production is complemented by a metabolic switch closely resembling the Warburg effect. Glucose uptake and cellular ATP concentration rise while mitochondrial respiration coupled ATP production declines. Mitochondria display cristae rearrangements closely reminiscent of ROS release and low respiratory activity (Arismendi-Morillo, 2011). This immediate metabolic change and redirection of glycolytic flow due to the induction of ATP-independent phospho-enol pyruvate phosphatase activity leads to activation of the mitochondrial glycerol3-phosphate shuttle via the inner membrane localized GPD2 (glycerol-3-phosphate dehydrogenase 2) (Kaminski et al., 2012; Vander Heiden et al., 2009). GPD2 knock-down abrogates the mROS production, NF-κB activation and the downstream NF-κB-dependent transcription (Kaminski et al., 2012; Vander Heiden et al., 2009). This suggests that the metabolic switch from mitochondrial respiration to aerobic glycolysis mediates mitochondrial ROS production. Activated GPD2 is shown to directly reduce ubiquinone and release mROS via complex I. Thus, GPD2 acts as a major player in T cell activation-induced ROS release during the metabolic switch. In addition to GPD2, TCR-triggered metabolic switch also activates another glycolytic enzyme, ADPGK (ADPdependent glucokinase). The PKC-dependent ADPGK activity is triggered shortly after TCR-mediated stimulation. Modulating the ADPGK levels by either knock-down or over-expression reveal the crucial role of ADPGK in activation-induced ROS production. Although ADPGK is an ER resident protein with its active site exposed on the cytosolic side, its activation could enhance the glycolytic flux and thus possibly contribute to mROS production (Kaminski et al., 2012; Vander Heiden et al., 2009).
5.7. SUMMARY ROS are well established to play a crucial role in cellular signal transduction and mitochondria as a source of endogenous ROS, are increasingly being evaluated. There are 11 different sites within mitochondria that act as centers of ROS production but till date our knowledge on ROS, T cell activation and T cell induced mROS production is limited to Complex I and III and to some extent complex IV. ROS is regulated tightly by antioxidant mechanisms within mitochondria that comprise antioxidant enzymes and ROS scavengers. There is growing interest in antioxidant-mediated mROS regulation in T cell activation process. Most of the studies are focused on SODs that reside within mitochondrial matrix. While the involvement of respiratory complexes in mROS production is convincing, one should remember all these studies are limited to in vitro conditions. Among the varied reasons for this limitation is the lack of highly sensitive experimental techniques that could measure compartmentalized ROS in a spatiotemporal manner. Further, the lack of knockout mouse models where mitochondrial ROS is compromised is another major limitation. This is because the respiratory complexes are indispensable in mice. Despite these limitations, new evidence of the crucial role of mitochondrial oxidants in T cell activation process is gradually emerging. Functional respiratory complex I (and complex III), and MnSOD activity as well as the metabolic switch from mitochondrial ATP to aerobic glycolysis triggering the GDP2 and ADPGK constitute the crucial players in T cell activation process. Nevertheless, more research is needed to further understand the in vivo molecular mechanisms of T cell activation-induced mitochondrial ROS production.
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