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Editor | xi Immune memory is a hallmark feature of adaptive immunity
.
The memory capacity of adaptive immunity enables the host to have a faster and more efficient immune response in the engine body when faced with the re-invasion of pathogenic microorganisms
.
Memory CD4 and CD8 T lymphocytes coordinate to construct T cell immunity [1], providing long-term and effective immune protection for the body
.
Memory T cells have the characteristics of resting, long life cycle, and high responsiveness to re-response
.
Memory CD8 T cells can maintain a stable number in the body for a longer period of time, while memory CD4 T cells show a slow and gradually decreasing number
.
In recent years, the research on the mechanism of CD8 T cell immune memory establishment and maintenance has made great progress [2], but the long-term maintenance mechanism of memory CD4 T cells is poorly understood
.
Understanding and exploring the establishment and long-term maintenance mechanism of CD4 T cell immune memory is an important task that needs to be in-depth
.
On December 23, 2021, the team of Professor Ye Lilin from the Army Military Medical University published a research paper entitled The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis in Nature Immunology, which reported the passage of mTORC2 signal.
A new mechanism to inhibit iron death and promote long-term maintenance of memory CD4 T cells
.
The researchers first established acute viral infection through lymphocytic choriomeningitis virus (LCMV), combined with bone marrow chimera model (BMC), in the memory CD4 T cell establishment phase (Day 21) and maintenance phase (Day 41), by knocking out Rictor gene to block mTORC2 signal, it is found that mTORC2 signal blocking will lead to a significant reduction of virus-specific memory CD4 T cells
.
At the same time, the LCMV virus-specific CD4 T cell SMARTA cell adoptive transfer model combined with the application of mTOR inhibitors (Torin1&Rapamycin) further verified that mTORC2 signaling is necessary for the maintenance of memory CD4 T cells
.
Next, the researchers found through experiments that the obstruction of mTORC2 signal did not change the proliferation ability of memory CD4 T cells, but caused a significant increase in the death of memory CD4 T cells
.
This method of death is not apoptosis, necroptosis, pyroptosis, etc.
, but iron death (ferroptosis), which has received increasing attention in recent years
.
The death of iron was first defined by the team of Professor Brent Stockwell of Columbia University in 2012 [3]
.
Iron death is a type of cell death caused by excessive accumulation of iron-dependent lipid peroxides on cell biofilms [3-4]
.
Iron death occurs due to the excessive oxidation of polyunsaturated fatty acids (PUFA) into toxic lipid peroxides (PL-PUFA-OOH).
This process relies on the free radicals provided by the Fenton reaction (hydroxyl).
radicals), and the substrate of the Fenton reaction in the cell is mainly derived from mitochondrial metabolism to produce reactive oxygen species (ROS) [4]
.
The researchers in this thesis verified the iron death table by using flow cytometry to detect lipid peroxide (Bodipy C11), GSEA to analyze the enrichment of the iron death pathway, and transmission electron microscopy to detect the morphological characteristics of iron death.
Type
.
At the same time, lipophilic peroxide hydroxyl radical scavenger (α-Tocopherol) or iron death specific inhibitor (Liproxstatin-1) can rescue the reduction of virus-specific memory CD4 T cells caused by blocked mTORC2 signaling
.
In addition, the researchers through the knockout and overexpression experiments of the key enzyme GPX4 in the iron death pathway, further proved that in the case of mTORC2 deficiency, the main form of memory CD4 T cell death is iron death
.
In terms of mechanism, the researchers found that memory CD4 T cells maintain a relatively low but continuous (tonic) mTORC2 signal activity under the influence of the IL-7/IL-7R signaling pathway
.
And this mTORC2-pAKTSer473-pGSK3βSer9 signal axis inhibits the occurrence of memory CD4 T cell iron death through two pathways
.
As shown in the following schematic diagram: On the one hand, mTORC2-pAKTSer473-pGSK3βSer9 regulates the binding of hexokinase (HK2) and ion channels on the mitochondrial membrane (VDAC) in the cytoplasm to maintain the normal function of mitochondria and avoid excessive accumulation of mitochondrial-derived ROS.
In turn, the occurrence of iron death is suppressed
.
On the other hand, mTORC2-pAKTSer473-pGSK3βSer9 regulates the nuclear transcription function of NRF2, a key factor in the oxidative stress pathway, thereby ensuring the expression levels of target genes (slc3a2, gclc, gclm) downstream of NRF2 that are involved in maintaining the activity of the GPX4 enzyme
.
Among them, SLC3A2 encoded by Slc3a2 is a key subunit of system xc-, an antiporter that transports cystine and cysteine, and provides raw materials for the synthesis of downstream reducing glutathione (GSH).
Gclc and Gclm coded GCLC And GCLM is the rate-limiting enzyme for the synthesis of GSH; and the mutual conversion of GSH and oxidized glutathione (GSSG) provides power for GPX4 to remove excessively accumulated lipid peroxides, and GPX4 exerts its anti-peroxidase activity Necessary conditions
.
In summary, this study reveals for the first time the role and mechanism of the mTORC2 pathway in the long-term maintenance of memory CD 4 T cells.
It is designed to develop long-acting vaccines and formulate treatments for the persistent pathogenic CD4 T cells in the body.
New strategies for immune diseases provide a new research foundation and ideas
.
The first author of this paper is Dr.
Wang Yifei, former Institute of Translational Medicine of Jinan University, now Dr.
Wang Yifei, School of Laboratory and Biotechnology, Southern Medical University, Dr.
Tian Qin, Institute of Immunology, Army Military Medical University, and Institute of Immunology, Army Military Medical University Dr.
Hao Yaxing
.
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
.
Original link: https://doi.
org/10.
1038/s41590-021-01090-1 Platemaker: 11 References 1 Gourley, TS, Wherry, EJ, Masopust, D.
& Ahmed, R.
Generation and maintenance of immunological memory.
Semin.
Immunol.
16, 323-333 (2004).
2 Martin MD, Badovinac VP.
Defining Memory CD8 T Cell.
Front Immunol.
2018;9:2692.
3 Dixon SJ, Lemberg KM, Lamprecht MR, et al.
Ferroptosis: an iron-dependent form of nonapoptotic cell death.
Cell.
2012;149(5):1060-1072.
4 Jiang X, Stockwell BR, Conrad M.
Ferroptosis: mechanisms, biology and role in disease.
Nat Rev Mol Cell Biol.
2021;22 (4):266-282.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated
.
.
The memory capacity of adaptive immunity enables the host to have a faster and more efficient immune response in the engine body when faced with the re-invasion of pathogenic microorganisms
.
Memory CD4 and CD8 T lymphocytes coordinate to construct T cell immunity [1], providing long-term and effective immune protection for the body
.
Memory T cells have the characteristics of resting, long life cycle, and high responsiveness to re-response
.
Memory CD8 T cells can maintain a stable number in the body for a longer period of time, while memory CD4 T cells show a slow and gradually decreasing number
.
In recent years, the research on the mechanism of CD8 T cell immune memory establishment and maintenance has made great progress [2], but the long-term maintenance mechanism of memory CD4 T cells is poorly understood
.
Understanding and exploring the establishment and long-term maintenance mechanism of CD4 T cell immune memory is an important task that needs to be in-depth
.
On December 23, 2021, the team of Professor Ye Lilin from the Army Military Medical University published a research paper entitled The kinase complex mTORC2 promotes the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis in Nature Immunology, which reported the passage of mTORC2 signal.
A new mechanism to inhibit iron death and promote long-term maintenance of memory CD4 T cells
.
The researchers first established acute viral infection through lymphocytic choriomeningitis virus (LCMV), combined with bone marrow chimera model (BMC), in the memory CD4 T cell establishment phase (Day 21) and maintenance phase (Day 41), by knocking out Rictor gene to block mTORC2 signal, it is found that mTORC2 signal blocking will lead to a significant reduction of virus-specific memory CD4 T cells
.
At the same time, the LCMV virus-specific CD4 T cell SMARTA cell adoptive transfer model combined with the application of mTOR inhibitors (Torin1&Rapamycin) further verified that mTORC2 signaling is necessary for the maintenance of memory CD4 T cells
.
Next, the researchers found through experiments that the obstruction of mTORC2 signal did not change the proliferation ability of memory CD4 T cells, but caused a significant increase in the death of memory CD4 T cells
.
This method of death is not apoptosis, necroptosis, pyroptosis, etc.
, but iron death (ferroptosis), which has received increasing attention in recent years
.
The death of iron was first defined by the team of Professor Brent Stockwell of Columbia University in 2012 [3]
.
Iron death is a type of cell death caused by excessive accumulation of iron-dependent lipid peroxides on cell biofilms [3-4]
.
Iron death occurs due to the excessive oxidation of polyunsaturated fatty acids (PUFA) into toxic lipid peroxides (PL-PUFA-OOH).
This process relies on the free radicals provided by the Fenton reaction (hydroxyl).
radicals), and the substrate of the Fenton reaction in the cell is mainly derived from mitochondrial metabolism to produce reactive oxygen species (ROS) [4]
.
The researchers in this thesis verified the iron death table by using flow cytometry to detect lipid peroxide (Bodipy C11), GSEA to analyze the enrichment of the iron death pathway, and transmission electron microscopy to detect the morphological characteristics of iron death.
Type
.
At the same time, lipophilic peroxide hydroxyl radical scavenger (α-Tocopherol) or iron death specific inhibitor (Liproxstatin-1) can rescue the reduction of virus-specific memory CD4 T cells caused by blocked mTORC2 signaling
.
In addition, the researchers through the knockout and overexpression experiments of the key enzyme GPX4 in the iron death pathway, further proved that in the case of mTORC2 deficiency, the main form of memory CD4 T cell death is iron death
.
In terms of mechanism, the researchers found that memory CD4 T cells maintain a relatively low but continuous (tonic) mTORC2 signal activity under the influence of the IL-7/IL-7R signaling pathway
.
And this mTORC2-pAKTSer473-pGSK3βSer9 signal axis inhibits the occurrence of memory CD4 T cell iron death through two pathways
.
As shown in the following schematic diagram: On the one hand, mTORC2-pAKTSer473-pGSK3βSer9 regulates the binding of hexokinase (HK2) and ion channels on the mitochondrial membrane (VDAC) in the cytoplasm to maintain the normal function of mitochondria and avoid excessive accumulation of mitochondrial-derived ROS.
In turn, the occurrence of iron death is suppressed
.
On the other hand, mTORC2-pAKTSer473-pGSK3βSer9 regulates the nuclear transcription function of NRF2, a key factor in the oxidative stress pathway, thereby ensuring the expression levels of target genes (slc3a2, gclc, gclm) downstream of NRF2 that are involved in maintaining the activity of the GPX4 enzyme
.
Among them, SLC3A2 encoded by Slc3a2 is a key subunit of system xc-, an antiporter that transports cystine and cysteine, and provides raw materials for the synthesis of downstream reducing glutathione (GSH).
Gclc and Gclm coded GCLC And GCLM is the rate-limiting enzyme for the synthesis of GSH; and the mutual conversion of GSH and oxidized glutathione (GSSG) provides power for GPX4 to remove excessively accumulated lipid peroxides, and GPX4 exerts its anti-peroxidase activity Necessary conditions
.
In summary, this study reveals for the first time the role and mechanism of the mTORC2 pathway in the long-term maintenance of memory CD 4 T cells.
It is designed to develop long-acting vaccines and formulate treatments for the persistent pathogenic CD4 T cells in the body.
New strategies for immune diseases provide a new research foundation and ideas
.
The first author of this paper is Dr.
Wang Yifei, former Institute of Translational Medicine of Jinan University, now Dr.
Wang Yifei, School of Laboratory and Biotechnology, Southern Medical University, Dr.
Tian Qin, Institute of Immunology, Army Military Medical University, and Institute of Immunology, Army Military Medical University Dr.
Hao Yaxing
.
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
.
Original link: https://doi.
org/10.
1038/s41590-021-01090-1 Platemaker: 11 References 1 Gourley, TS, Wherry, EJ, Masopust, D.
& Ahmed, R.
Generation and maintenance of immunological memory.
Semin.
Immunol.
16, 323-333 (2004).
2 Martin MD, Badovinac VP.
Defining Memory CD8 T Cell.
Front Immunol.
2018;9:2692.
3 Dixon SJ, Lemberg KM, Lamprecht MR, et al.
Ferroptosis: an iron-dependent form of nonapoptotic cell death.
Cell.
2012;149(5):1060-1072.
4 Jiang X, Stockwell BR, Conrad M.
Ferroptosis: mechanisms, biology and role in disease.
Nat Rev Mol Cell Biol.
2021;22 (4):266-282.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated
.
