T cell lipid peroxidation induces ferroptosis and prevents immunity to infection

Abstract

Matsushita et al. investigated the role of the selenoenzyme glutathione peroxidae 4 (Gpx4) in T cell responses and found that loss of Gpx4 results in an intrinsic T cell developmental defect in the periphery, which leads to a failure to expand and protect from acute viral and parasitic infection.The defects were rescued with dietary supplementation of vitamin E. The Gp4−/− T cells accumulate membrane lipid peroxides and undergo cell death by ferroptosis.

Ferroptosis: process and function

“…23 Indeed, several normal Ras wild-type cells such as kidney tubule cells, T cells, and fibroblasts are sensitive to erastin. 5,22,[26][27][28] Even in some cases, overexpression of mutant Ras in rhabdomyosarcoma cells (e.g., RMS13 cells) promotes ferroptosis resistance to erastin and RLS3. 29 TFR1: Compared with ferroptosis-resistant cells (e.g., BJ cells), the expression of TFR1 is upregulated in ferroptosissensitive cells (e.g., BJeLR cells).…”

“…26 GPX4 − / − T cells rapidly accumulate lipid peroxides and die by ferroptosis, but not other types of RCD. 26 Inducible neuron-specific GPX4 knockout mice have neuronal loss in the brain partly due to induction of ferroptosis. 34 In contrast, mice with deletion of GPX4 in hematopoietic cells develop anemia due to induction of RIP3-dependent necroptosis, but not apoptosis and ferroptosis.…”

Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors

“…14 To investigate the mechanism of cell death we have targeted variable regulatory elements of programmed cell death pathways ( Figure 4C). Surprisingly, ferroptosis inhibition using the small inhibitor Fer-1 did not prevent cell death in Gpx4 D erythroid cultures and even reduced the viability of control cells, whereas erastin-and RLS3-induced ferroptosis was completely rescued in control cells and only partially rescued in Gpx4 D cells using the same concentration (supplemental Figure 3A).…”

“…10,11 Moreover, Gpx4 controls caspase-independent cell death in neurons, 12 photoreceptor cells, 13 and T cells. 14 Ferroptosis is a nonapoptotic form of cell death involving the production of iron-dependent ROS. 15 It was recently noted that the oncogenic RAS-selective lethal small molecule erastin triggers ferroptosis via inhibiting cysteine uptake by the cysteine/glutamate antiporter, leading to iron-dependent accumulation of lethal lipid ROS and eventually to ferroptotic cell death, which is morphologically, biochemically, and genetically distinct from apoptosis and necrosis.…”

“…16 In addition to the cancer cells, Gpx4 depletion leads to massive cell death through the induction of lipid peroxidation and ferroptotic machinery in renal tubular epithelia 17 and in T cells. 14 In addition to apoptosis and ferroptosis, several other forms of programmed cell death have been described, including poly(adenosine 59-diphosphate ribose) polymerase (PARP)1-dependent and apoptosisinducing factor 1-dependent parthanatos, caspase 1-dependent pyroptosis, and receptor-interacting protein (RIP) 1-dependent necroptosis. 15,[18][19][20][21] Necroptosis can be triggered by ligation of death receptors such as CD95, tumor necrosis factor (TNF) receptor 1 and 2 (TNFR1 and 2), as well as TNF-related apoptosis-inducing ligand receptor 1 and 2.…”