Selenium-GPX4 axis protects follicular helper T cells from ferroptosis
On 19 August, 2021, professor Di Yu from University of Queensland Diamantina Institute, professor Zheng Liu from Huazhong University of Science and Technology and professor Wenhong Zhang from Fudan University published a paper titled Selenium‒GPX4 axis protects follicular helper T cells from ferroptosis on Nature Immunology.
Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells that essentially support germinal center responses where high-affiffiffinity and long-lived humoral immunity is generated. The regulation of TFH cell survival remains unclear. Here we report that TFH cells show intensifified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferropto sis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxi dase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for TFH cell survival. The deletion of GPX4 in T cells selectively abrogated TFH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased TFH cell numbers and promoted antibody responses in immunized mice and young adults after inflfluenza vaccination. Our fifindings reveal the central role of the selenium‒GPX4‒ferroptosis axis in regulating TFH homeostasis, which can be targeted to enhance TFH cell function in infection and following vaccination.
Cell death is the ultimate fate of all cells, and the method of cell death is a major research hotspot in the fifield of biomedicine. We have introduced cell pyrolysis before, so, besides apoptosis and cell pyrolysis, is there any other way for programmed cell death? The concept of "ferroptosis" was fifirst proposed by Brent R. Stockwell's team in 2012. Ferroptosis is oxidative cell death induced by small molecules, which is dependent on iron ions. It is caused by the imbalance between the production and degradation of lipid reactive oxygen species(ROS) in cells. Ferroptosis inducers directly or indirectly act on glutathione peroxidase(GPXs) through difffferent pathways, resulting in decreased antioxidant capacity, accumulation of ROS, and ultimately cell death in the form of oxidative and non-apoptotic cells.
Mechanism of ferroptosis
1. Inhibition of GPX4: GPX4 inhibits lipid peroxidation, and ferroptosis is more likely to occur if GPX4 expression is down-regulated in cells.
2. Inhibition of cystine/glutamate antiporter(systemXC-): The level of glutamate affffects the function of systemXC-. The high concentration of extracellular glutamate inhibit systemXC- and induce ferroptosis.
3. Mediation of p53: p53 inhibits the uptake of cystine by down-regulating the expression of the systemXC- component SLC7A11, resulting in a decrease in GPXs activity, reducing cellular antioxidant capacity, and enhancing sensitivity of ferroptosis.
