Journal Article

The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis

Chen, Xiangyu, Yin Zhinan, Hu, Jianjun, Xu Lifan, Zhou, Xinyuan, Yao, Wei, Tian Qin, Tang Jianfang, Wang, Yifei, Hao Yaxing, Luo, Yuan, Li, Zhirong, Lu Jinjin, Wu Yuzhang, Huang Qizhao, Zhengping, Wei, Chen, Cheng, Ye Lilin, Lei Shun, Yao, Lin, Hu, Li, Xu, Jianqing, Wu, Qing

2022

Overview

Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3β kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2–AKT–GSK3β axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.Wang et al. show that the Rictor-dependent mTORC2–Akt pathway is needed to maintain CD4+ memory cells. This axis acts, in part, by suppressing mitoROS generation and subsequent oxidation of membrane phospholipids, which then triggers cell death by ferroptosis.

• Publisher: Nature Publishing Group
• Subject: AKT protein / Apoptosis / CD4 antigen / Cell death / Ferroptosis / Glutathione peroxidase / Immunological memory / Inactivation / Lipid peroxidation / Longevity / Lymphocytes / Lymphocytes T / Memory cells / Mitochondria / Oxidation / Peroxidation / Phospholipids / Phosphorylation / Protein-serine/threonine kinase / Rapamycin / Reactive oxygen species / TOR protein / Viruses