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Follicular helper T (TFH) cells are a unique subset of CD4+ T cells.
Their main role is to help B cells establish germinal center responses and produce high-affinity antibodies [1]
.
Vaccination is currently one of the most effective strategies to prevent viral infection and disease.
Its core is to induce TFH cell-mediated humoral immune response and immune memory [2]
.
However, there is still a lack of effective methods to enhance the function of TFH in clinical practice.
The reason is that the mechanism of maintaining the homeostasis of TFH cells is unknown
.
For example, how is the death of TFH cells regulated? On August 19, 2021, Liu Zheng's team from Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology and Yu Di's team from the University of Queensland carried out interdisciplinary cooperation and published the title Selenium-GPX4 axis protects follicular helper T cells in Nature Immunology.
From ferroptosis article, it is found that iron death is the main way of death of TFH cells.
The absence of the main iron death antagonist protein GPX4 in T cells will lead to the loss of TFH cells and extremely low antibody response
.
On the contrary, daily dietary selenium supplementation can up-regulate the selenoprotein GPX4, protect TFH cells from iron death, and enhance antibody immune response
.
Reactive oxygen species (ROS) are a group of oxygen-containing molecules with strong chemical activity, which play a pivotal role in the activation, proliferation and death of T cells [3]
.
Excessive ROS in the cell cytoplasm can react with iron ions to generate lipid ROS, which drives programmed cell death-ferroptosis [4]
.
Glutathione peroxidase 4 (GPX4) is the only enzyme that can remove lipid ROS on biological membranes and is a crucial regulator of iron death [5]
.
First, the researchers used transmission electron microscopy and flow cytometry to observe that both mouse and human TFH cells exhibited iron death characteristics, including shrunken and damaged mitochondria, high levels of lipid ROS accumulation, etc.
(Figure 1)
.
Gene knockout and inhibition of GPX4 activity are the most classic methods to cause iron death
.
The researchers constructed mice lacking GPX4 specifically for T cells and found that in the immune model, the lack of GPX4 resulted in a significant decrease in the number and proportion of TFH cells, accompanied by the loss of germinal center B (BGC) cells and high-affinity antibodies (Figure 2 )
.
Figure 1.
Shrinkage and damage of mitochondria in TFH cells under transmission electron microscope.
Figure 2.
Immunofluorescence shows that T-cell specific deficiency of GPX4 (T-KO) mice lacks BGC cells and excessive accumulation of lipid ROS leads to iron death.
The direct cause, what factors cause it to accumulate in TFH cells? In order to effectively optimize antibody production, TFH frequently interacts with BGC cells.
This effect causes the surface receptor signals of T cells, especially T cell receptor signals, to be repeatedly activated
.
The researchers further revealed that the TFH-BGC cell interaction significantly increased the lipid ROS level of TFH cells and their sensitivity to iron death
.
Based on the discovery of this important mechanism for regulating the homeostasis of TFH cells, the researchers further explored interventions to regulate the iron death of TFH cells
.
The researchers found that iron death inhibitors significantly protect TFH cells in immunized mice, thereby up-regulating the number of BGC cells and increasing the production of high-affinity antibodies, indicating that intervention in TFH cell iron death is of great significance to antibody responses
.
Selenium is one of the essential trace elements of the human body, and it plays an important role in regulating the body's immune balance and preventing cancer
.
Taking advantage of the properties of GPX4 as a selenoprotein and the key role of selenium in its enzymatic activity, researchers supplemented with selenium through diet and drinking water to reveal that selenium supplementation significantly increased the level of GPX4 protein and the function of TFH and BGC cells in mice, suggesting selenium supplementation It may promote protective antibody response, such as vaccine immunity
.
Based on animal studies, researchers designed a clinical selenium supplement test to explore the effects of selenium on human humoral immunity
.
Healthy adult volunteers were randomly divided into two groups: selenium supplementation and ordinary diet
.
After 30 days of selenium supplementation or a control diet, all volunteers were vaccinated with seasonal influenza vaccine
.
Researchers found that selenium supplementation significantly increased the expression of immune cells GPX4 protein, and at the same time significantly increased the activity of TFH cells after vaccination, thereby increasing the titer of neutralizing antibodies against influenza virus
.
The above results provide an important basis for scientifically supplementing selenium in daily diet and improving human antibody immune response
.
Professor Liu Zheng and Professor Yu Di conducted a series of innovative studies on the role of TFH/TFR cells in respiratory allergic diseases, and found that type II TFH and TFR cells bidirectionally regulate IgE production in patients with allergic rhinitis It is proposed that the imbalance of type II TFH/TFR cells is an important immune mechanism for the occurrence of allergic rhinitis (in the Journal of Allergy and Clinical Immunology in 2018 and 2019, consecutively published in Allergy in 2020 and 2021)
.
This latest collaborative research result expands the understanding of TFH cell homeostasis control, especially the mode of death, and has important scientific significance and clinical value for the optimization and development of targeted respiratory disease treatment strategies, and is useful for vaccine development and vaccines.
Effective vaccination provides a new scientific basis and practical intervention measures, and brings new hopes for defeating the new crown and other infectious diseases
.
Dr.
Yao Yin from Wuhan Tongji Hospital, Dr.
Chen Zhian from the University of Queensland, and Dr.
Zhang Hao from Shandong Analysis and Testing Center are the co-first authors of the paper
.
Professor Yu Di and Professor Liu Zheng are the co-corresponding authors
.
Original link: https://doi.
org/10.
1038/s41590-021-00996-0 Platemaker: 11 References 1.
Deng J, Wei Y, Fonseca VR, Graca L, Yu D.
T follicular helper cells and T follicular regulatory cells in rheumatic diseases.
Nat Rev Rheumatol 2019; 15:475-490.
2.
Deng J, Chen Q, Chen Zet al.
The metabolic hormone leptin promotes the function of T(FH) cells and supports vaccine responses.
Nat Commun 2021; 12:3073.
3.
Franchina DG, Dostert C, Brenner D.
Reactive Oxygen Species: Involvement in T Cell Signaling and Metabolism.
Trends Immunol 2018; 39:489-50 2.
4.
Dixon SJ, Lemberg KM, Lamprecht MRet al.
Ferroptosis: An Iron- Dependent Form of Nonapoptotic Cell Death.
Cell 2012; 149:1060-1072.
5.
Stockwell BR, Friedmann Angeli JP, Bayir Het al.
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease.
Cell 2017; 171:273- 285.
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. .
Their main role is to help B cells establish germinal center responses and produce high-affinity antibodies [1]
.
Vaccination is currently one of the most effective strategies to prevent viral infection and disease.
Its core is to induce TFH cell-mediated humoral immune response and immune memory [2]
.
However, there is still a lack of effective methods to enhance the function of TFH in clinical practice.
The reason is that the mechanism of maintaining the homeostasis of TFH cells is unknown
.
For example, how is the death of TFH cells regulated? On August 19, 2021, Liu Zheng's team from Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology and Yu Di's team from the University of Queensland carried out interdisciplinary cooperation and published the title Selenium-GPX4 axis protects follicular helper T cells in Nature Immunology.
From ferroptosis article, it is found that iron death is the main way of death of TFH cells.
The absence of the main iron death antagonist protein GPX4 in T cells will lead to the loss of TFH cells and extremely low antibody response
.
On the contrary, daily dietary selenium supplementation can up-regulate the selenoprotein GPX4, protect TFH cells from iron death, and enhance antibody immune response
.
Reactive oxygen species (ROS) are a group of oxygen-containing molecules with strong chemical activity, which play a pivotal role in the activation, proliferation and death of T cells [3]
.
Excessive ROS in the cell cytoplasm can react with iron ions to generate lipid ROS, which drives programmed cell death-ferroptosis [4]
.
Glutathione peroxidase 4 (GPX4) is the only enzyme that can remove lipid ROS on biological membranes and is a crucial regulator of iron death [5]
.
First, the researchers used transmission electron microscopy and flow cytometry to observe that both mouse and human TFH cells exhibited iron death characteristics, including shrunken and damaged mitochondria, high levels of lipid ROS accumulation, etc.
(Figure 1)
.
Gene knockout and inhibition of GPX4 activity are the most classic methods to cause iron death
.
The researchers constructed mice lacking GPX4 specifically for T cells and found that in the immune model, the lack of GPX4 resulted in a significant decrease in the number and proportion of TFH cells, accompanied by the loss of germinal center B (BGC) cells and high-affinity antibodies (Figure 2 )
.
Figure 1.
Shrinkage and damage of mitochondria in TFH cells under transmission electron microscope.
Figure 2.
Immunofluorescence shows that T-cell specific deficiency of GPX4 (T-KO) mice lacks BGC cells and excessive accumulation of lipid ROS leads to iron death.
The direct cause, what factors cause it to accumulate in TFH cells? In order to effectively optimize antibody production, TFH frequently interacts with BGC cells.
This effect causes the surface receptor signals of T cells, especially T cell receptor signals, to be repeatedly activated
.
The researchers further revealed that the TFH-BGC cell interaction significantly increased the lipid ROS level of TFH cells and their sensitivity to iron death
.
Based on the discovery of this important mechanism for regulating the homeostasis of TFH cells, the researchers further explored interventions to regulate the iron death of TFH cells
.
The researchers found that iron death inhibitors significantly protect TFH cells in immunized mice, thereby up-regulating the number of BGC cells and increasing the production of high-affinity antibodies, indicating that intervention in TFH cell iron death is of great significance to antibody responses
.
Selenium is one of the essential trace elements of the human body, and it plays an important role in regulating the body's immune balance and preventing cancer
.
Taking advantage of the properties of GPX4 as a selenoprotein and the key role of selenium in its enzymatic activity, researchers supplemented with selenium through diet and drinking water to reveal that selenium supplementation significantly increased the level of GPX4 protein and the function of TFH and BGC cells in mice, suggesting selenium supplementation It may promote protective antibody response, such as vaccine immunity
.
Based on animal studies, researchers designed a clinical selenium supplement test to explore the effects of selenium on human humoral immunity
.
Healthy adult volunteers were randomly divided into two groups: selenium supplementation and ordinary diet
.
After 30 days of selenium supplementation or a control diet, all volunteers were vaccinated with seasonal influenza vaccine
.
Researchers found that selenium supplementation significantly increased the expression of immune cells GPX4 protein, and at the same time significantly increased the activity of TFH cells after vaccination, thereby increasing the titer of neutralizing antibodies against influenza virus
.
The above results provide an important basis for scientifically supplementing selenium in daily diet and improving human antibody immune response
.
Professor Liu Zheng and Professor Yu Di conducted a series of innovative studies on the role of TFH/TFR cells in respiratory allergic diseases, and found that type II TFH and TFR cells bidirectionally regulate IgE production in patients with allergic rhinitis It is proposed that the imbalance of type II TFH/TFR cells is an important immune mechanism for the occurrence of allergic rhinitis (in the Journal of Allergy and Clinical Immunology in 2018 and 2019, consecutively published in Allergy in 2020 and 2021)
.
This latest collaborative research result expands the understanding of TFH cell homeostasis control, especially the mode of death, and has important scientific significance and clinical value for the optimization and development of targeted respiratory disease treatment strategies, and is useful for vaccine development and vaccines.
Effective vaccination provides a new scientific basis and practical intervention measures, and brings new hopes for defeating the new crown and other infectious diseases
.
Dr.
Yao Yin from Wuhan Tongji Hospital, Dr.
Chen Zhian from the University of Queensland, and Dr.
Zhang Hao from Shandong Analysis and Testing Center are the co-first authors of the paper
.
Professor Yu Di and Professor Liu Zheng are the co-corresponding authors
.
Original link: https://doi.
org/10.
1038/s41590-021-00996-0 Platemaker: 11 References 1.
Deng J, Wei Y, Fonseca VR, Graca L, Yu D.
T follicular helper cells and T follicular regulatory cells in rheumatic diseases.
Nat Rev Rheumatol 2019; 15:475-490.
2.
Deng J, Chen Q, Chen Zet al.
The metabolic hormone leptin promotes the function of T(FH) cells and supports vaccine responses.
Nat Commun 2021; 12:3073.
3.
Franchina DG, Dostert C, Brenner D.
Reactive Oxygen Species: Involvement in T Cell Signaling and Metabolism.
Trends Immunol 2018; 39:489-50 2.
4.
Dixon SJ, Lemberg KM, Lamprecht MRet al.
Ferroptosis: An Iron- Dependent Form of Nonapoptotic Cell Death.
Cell 2012; 149:1060-1072.
5.
Stockwell BR, Friedmann Angeli JP, Bayir Het al.
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease.
Cell 2017; 171:273- 285.
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. .
