Nat Immunol Multi-unit cooperation of Army Military Medical University, Ye Lilin/Yin Zhinan/Xu Jianqing reveals a new mechanism of virus-specific CD4+ T cell immune memory maintenance

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iNature antigen-specific memory CD4+ T cells can persist and provide rapid and effective protection to prevent microbial reinfection
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However, the mechanism of long-term maintenance of the memory CD4+ T cell pool remains largely unknown
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On December 23, 2021, Ye Lilin of Army Military Medical University, Yin Zhinan of Jinan University and Xu Jianqing of Fudan University jointly published a study titled "The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis" in Nature Immunology.
The paper, the study used a mouse model of lymphocytic choriomeningitis virus (LCMV) acute infection and found that mTORC2 is essential for the long-term persistence of virus-specific memory CD4+ T cells
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The perturbation of mTORC2 signal in the memory phase leads to a huge loss of virus-specific memory CD4+ T cells, which is a unique regulated cell death (RCD), iron death
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In terms of mechanism, mTORC2 inactivation leads to impaired phosphorylation of downstream AKT and GSK3β kinases, which induces abnormal mitochondrial reactive oxygen species (ROS) accumulation and subsequently leads to lipid peroxidation caused by iron death in virus-specific memory CD4+ T cells; In addition, disruption of this signaling cascade also inhibits glutathione peroxidase 4 (GPX4), which is the main scavenger of lipid peroxidation
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Therefore, the mTORC2-AKT-GSK3β axis acts as a key signal center, which promotes the lifespan of virus-specific memory CD4+ T cells by preventing iron death
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CD4+ helper T (TH) cells play a central role in coordinating adaptive immune responses
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In order to respond to and adapt to various immune microenvironments, the initial CD4+ T cells differentiate into different effector lineages, including TH1, TH2, TH17 and follicular helper T (TFH) cells that specifically help B cell responses
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In the case of acute viral infection, virus-specific initial CD4+ T cells differentiate into effector TH1 and TFH cells, and promote the virus by providing key “help” for virus-specific CD8+ T cells (through TH1) and B cells (through TFH) Clear: After clearing the viral antigen, the effector TH1 and TFH cells further differentiate into the corresponding memory TH lineage
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At present, the molecular pathway to maintain the virus-specific memory CD4+ T cell pool is largely undefined
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The serine/threonine kinase mTOR determines the fate of T cell differentiation
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mTOR kinase can be assembled into two complexes with different structures and functions, mTORC1 and mTORC2, they share the same catalytic subunit mTOR, but the difference is two scaffold subunits, Raptor of mTORC1 and Rictor of mTORC2.

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The subclinical dose of rapamycin inhibits mTORC1 signaling by promoting oxidative phosphorylation and EOMES expression, which is conducive to the differentiation of memory CD8+ T cells
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In addition, it is reported that defects in mTORC2 signaling can promote the formation of memory CD8+ T cells through metabolic reprogramming and FOXO1-dependent pathways
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Similarly, it is reported that inhibition of mTORC1 signal by rapamycin can also enhance the differentiation of memory TH1 and TFH
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Whether and how mTORC2 regulates CD4+ T cell memory is still unknown, although mTORC2 has been found to be essential for TFH differentiation and functional maturation
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Apoptosis is a classic form of programmed cell death, and it plays a leading role in the turnover of memory T cells in a resting state
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Recently, a new type of RCD, iron death, is driven by iron-dependent lethal accumulation of membrane lipid peroxidation
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When the polyunsaturated fatty acid (PUFA) tail of membrane phospholipid is over-oxidized to toxic lipid peroxide (PL-PUFA-OOH), iron death will occur under static conditions
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Mitochondria produce most of the endogenous ROS, including superoxide anions and hydrogen peroxide (O2•– and H2O2)
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Both are used as the substrate of Fenton reaction to generate hydroxyl radicals (OH•), which promote the spread of phospholipid peroxidation and the degradation of membrane lipids
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Glutathione-dependent peroxidase GPX4 can convert toxic PL-PUFA-OOH into non-toxic PL-PUFA-OH by oxidizing glutathione (GSH) to glutathione disulfide (GSSG) ) To prevent membrane lipid peroxidation
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Disorders of various metabolic pathways are related to iron death
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Given that mTORC2 signal transduction coordinates a variety of metabolic pathways, it is of great significance to explore the role of mTORC2 in regulating the iron death of memory CD4+ T cells
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Here, the study examined the function of the mTORC2 pathway in antigen-specific memory CD4+ T cells in a mouse model of acute LCMV infection
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Research results show that mTORC2 signaling plays a vital role in the long-term maintenance of virus-specific memory CD4+ T cells by preventing iron death-induced cell death
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The first authors of this paper are Dr.
Wang Yifei from the former Institute of Translational Medicine of Jinan University and now from the School of Laboratory and Biotechnology of Southern Medical University, Dr.
Tian Qin from the Institute of Immunology of the Army Military Medical University, and the Institute of Immunology of the Army Military Medical University Dr.
Hao Yaxing
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The corresponding authors are Professor Ye Lilin from the Institute of Immunology of Army Military Medical University, Professor Yin Zhinan from the Institute of Translational Medicine of Jinan University, and Professor Xu Jianqing from the Institute of Biomedicine, Fudan University
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