T cell lipid peroxidation induces ferroptosis and prevents immunity to infection

“Cystine in the extracellular space is transported exclusively by the xc and converted to cysteine, which facilitates the synthesis of intracellular glutathione (GSH), a major cellular antioxidant (Fahey and Sundquist, 1991).”

“The central importance for cellular physiology and normal development of the cytosolic form is highlighted by the embryonic lethality observed in mice with a homozygous Gpx4 deletion (Yant et al., 2003).”

“After immune responses to infections, T cell populations are controlled and maintained by programmed cell death, one of which is initiated by the death receptor ligation, involving Fas-associated death domain protein (FADD) and caspase 8 (Ashkenazi and Dixit, 1998).”

“Concurrently, it is well appreciated that ROS are at the interface of several cell signaling pathways that regulate cell proliferation, differentiation, and death (D’Autréaux and Toledano, 2007; Finkel, 2011; Ray et al., 2012).”

“Although apoptosis has long been considered the primary form of programmed cell death, recent studies have identified that necroptosis can also occur by inactivation of caspase 8 and complex formation of RIP kinase 1 and 3 (Cho et al., 2009; Declercq et al., 2009).”

“ERK1/2 phosphorylation upon TCR triggering depends on the generation of hydrogen peroxide and stimulates glutamine uptake (Devadas et al., 2002; Carr et al., 2010).”

“Indeed, RAS–RAF–MEK signaling has been shown to be required for erastin-induced ferroptosis of tumor cells (Yagoda et al., 2007).”

“Although apoptosis has long been considered the primary form of programmed cell death, recent studies have identified that necroptosis can also occur by inactivation of caspase 8 and complex formation of RIP kinase 1 and 3 (Cho et al., 2009; Declercq et al., 2009).”

“Indeed, oxidative stress has been implicated in aging (Lambert et al., 2007) and development of a variety of diseases, including cancer (Toyokuni et al., 1995), type 2 diabetes (Brownlee, 2001), atherosclerosis (Galkina and Ley, 2009), and neurodegeneration (Lin and Beal, 2006).”

“TCR stimulation has been shown to induce production of discrete species of ROS (i.e., hydrogen peroxide and superoxide anion), involving a phagocyte type NADPH oxidase expressed by T cells and the FAS pathway (Devadas et al., of bacteria, whereas groups of mice undergoing primary infection were all moribund and had to…”

“Erastin-induced ferroptotic death of RAS mutant tumor cells has been reported to prevent glutamate-induced neurotoxicity (Dixon et al., 2012), regulated by Gpx4 (Yang et al., 2014).”

“T cells lacking caspase 8 or its adaptor protein FADD exhibit defective T cell homeostasis, clonal expansion, contraction, and antiviral responses (Walsh et al., 1998; Ch’en et al., 2011).”

“2+) 12/15-lipoxygenase–induced lipid peroxidation that triggers apoptosis-inducing-factor (AIF)–mediated cell death in fibroblasts in vitro (Seiler et al., 2008).”

“Recently, T cell activation, expansion, and effector function have been shown to involve ROS as an important signaling molecule (Wang and Green, 2012; Pearce and Pearce, 2013; Sena et al., 2013).”

“TGpx4/Gpx4 and tamGpx4/Gpx4 mice were generated by crossing Gpx4fl/fl mice (C57BL/6; n > 8; Seiler et al., 2008) to Cd4-cre (JAX; Lee et al., 2001) and Ert2-Cre (Hameyer et al., 2007), respectively.”

“TCR stimulation has been shown to induce production of discrete species of ROS (i.e., hydrogen peroxide and superoxide anion), involving a phagocyte type NADPH oxidase expressed by T cells and the FAS pathway (Devadas et al., of bacteria, whereas groups of mice undergoing primary infection were all moribund and had to…”

“…mice (obtained originally from the late J. Tschopp with kind permission of Vishva M. Dixit, Genentech, South San Francisco, CA; Newton et al., 2004), and P14 (JAX; Pircher et al., 1989) were crossed to TGpx4/Gpx4 to generate TGpx4/Gpx4/Alox15/, TGpx4/Gpx4/ Ripk3/, and P14Gpx4/Gpx4, respectively.”

“ERK1/2 phosphorylation upon TCR triggering depends on the generation of hydrogen peroxide and stimulates glutamine uptake (Devadas et al., 2002; Carr et al., 2010).”

“Disruption of this redox equilibrium leads to increased ROS levels, which can threaten the integrity of various biomolecules including DNA, proteins, lipoproteins and lipids, thereby causing aberrant cell death and tissue deterioration (Marnett, 2002).”

“Strains of Alox15/ (JAX; Sun and Funk, 1996), Ripk3/ mice (obtained originally from the late J. Tschopp with kind permission of Vishva M. Dixit, Genentech, South San Francisco, CA; Newton et al., 2004), and P14 (JAX; Pircher et al., 1989) were crossed to TGpx4/Gpx4 to generate TGpx4/Gpx4/Alox15/, TGpx4/Gpx4/ Ripk3/, a…”

“…Gpx4-deficient T cell cultured with pharmacological inhibitors of autophagy, apoptosis, and necroptosis, such as 3-methyladenine, z-VAD-FMK, a pan-caspase inhibitor, and necrostatin-1, which binds to RIPk1 and blocks DR-induced necroptosis (Degterev et al., 2005), failed to prevent the cell death.”

“Recently, T cell activation, expansion, and effector function have been shown to involve ROS as an important signaling molecule (Wang and Green, 2012; Pearce and Pearce, 2013; Sena et al., 2013).”

“Vitamin E is known to function as a lipid-soluble antioxidant that eliminates peroxyl radicals and prevents the propagation of lipid peroxidation (Tappel, 1972).”

“Erastin-induced ferroptotic death of RAS mutant tumor cells has been reported to prevent glutamate-induced neurotoxicity (Dixon et al., 2012), regulated by Gpx4 (Yang et al., 2014).”

“Because naive T cells do not express xc, they are metabolically dependent on APCs to maintain homeostatic balance and undergo T cell activation and proliferation (Angelini et al., 2002).”

“Absence of such interactions results in death of CD8+ T cells within a few days, whereas CD4+ T cells survive with a half-life of months (Rooke et al., 1997; Tanchot et al., 1997; Selin et al., 1999), which may explain why Gpx4 is predominantly required for survival of peripheral CD8+ T cell in homeostasis.”

“Although it has become widely understood that T cells can in fact up-regulate xc upon activation, T cells in the early stages of activation still require cysteine from other sources (Levring et al., 2012).”

“Recently, T cell activation, expansion, and effector function have been shown to involve ROS as an important signaling molecule (Wang and Green, 2012; Pearce and Pearce, 2013; Sena et al., 2013).”

“T cells lacking caspase 8 or its adaptor protein FADD exhibit defective T cell homeostasis, clonal expansion, contraction, and antiviral responses (Walsh et al., 1998; Ch’en et al., 2011).”

“In agreement with these findings, pharmacological inhibition of 12/15-lipoxygenase partially protected 2002; Jackson et al., 2004).”

“Absence of such interactions results in death of CD8+ T cells within a few days, whereas CD4+ T cells survive with a half-life of months (Rooke et al., 1997; Tanchot et al., 1997; Selin et al., 1999), which may explain why Gpx4 is predominantly required for survival of peripheral CD8+ T cell in homeostasis.”

“T reg cells are known to secrete more thioredoxin-1, an antioxidant, than effector T cells, and therefore may be more resistant to ROS-induced damage (Mougiakakos et al., 2011).”

“Also, studies have suggested a synergistic relationship between selenium and vitamin E to inhibit lipid peroxidation (Navarro et al., 1998; Beck et al., 2003).”

“Indeed, oxidative stress has been implicated in aging (Lambert et al., 2007) and development of a variety of diseases, including cancer (Toyokuni et al., 1995), type 2 diabetes (Brownlee, 2001), atherosclerosis (Galkina and Ley, 2009), and neurodegeneration (Lin and Beal, 2006).”

“One of the eight members of the glutathione peroxidase (Gpx) family, Gpx4, has been reported as a unique antioxidant enzyme for its ability to directly reduce phospholipid hydroperoxides and oxidized lipoproteins to their respective lipid-alcohol within biomembranes (Thomas et al., 1990; Sattler et al., 1994).”

“Earlier studies have suggested that Gpx4 inactivation in murine fibroblasts result in apoptosis-inducing factor (AIF)-mediated cell death as a consequence of lipid peroxide accumulation catalyzed specifically by 12/15-lipoxygenase in vitro (Seiler et al., 2008; Schneider et al., 2010).”

“Moreover, mitochondria are a major source of ROS and mitochondrial ROS is essential for T cell activation, expansion and effector function (Sena et al., 2013; Yi et al., 2006).”

“As it has been reported that normoxia increases oxygen radicals and promotes hydrogen peroxides generation (Fan et al., 2008), the effect in vitro suggests that the Gpx4deficient T cells acquire damage already ex vivo as a consequence of high oxygen levels in normoxic conditions, which provoked the…”

“Also, studies have suggested a synergistic relationship between selenium and vitamin E to inhibit lipid peroxidation (Navarro et al., 1998; Beck et al., 2003).”

“Concurrently, it is well appreciated that ROS are at the interface of several cell signaling pathways that regulate cell proliferation, differentiation, and death (D’Autréaux and Toledano, 2007; Finkel, 2011; Ray et al., 2012).”

“acute renal or hepatic injury [547, 563, 589], neurodegeneration [550, 590, 591], and defective immunity to infection [567], all of which can be prevented or mitigated by ferroptosis-inhibiting strategies.”

“Thus, the most important objective in the study of ferroptosis is to identify the downstream signaling pathways or executors of iron-dependent ROS metabolism to distinguish ferroptosis from other types of RCD. Induction of ferroptosis by drugs has been shown to inhibit cancer cell growth in both a Ras-dependent and -i…”