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▎This article was reproduced from "Tsinghua Immunity" on February 18, 2021.
Nature published an online publication of Professor Qi Hai’s research group from the Institute of Immunology of Tsinghua University entitled Affinity-coupled CCL22 promotes positive selection in germinal centres ("Affinity-coupled CCL22 promotes positive selection in germinal centres" CCL22 promotes forward screening of germinal centers") research paper.
The study found that in the antibody immune response, the chemokine CCL22 promotes a new mechanism for the production of high-affinity antibodies, which provides a potential new target for future improved vaccine development.
Antibodies are an important immune mechanism for the body to resist the invasion of viruses, bacteria and other pathogens.
Vaccines that induce protective antibodies are an important weapon to curb the spread of many pathogens, including the new coronavirus.
Protective antibodies not only need to specifically recognize the pathogen (antigen), but also need to bind to the antigen tightly (high affinity) in order to block the infection of cells and tissues by the pathogen.
Antibodies are produced by B cells, but there are only a few B cells that can produce high-affinity antibodies; they occur in lymphoid tissues called "germinal centers", and are selected from many B cells with different affinities through a Darwinian evolutionary screening process Selected from among them, and then differentiated into plasma cells (B cells that continuously secrete antibodies).
This Darwinian evolutionary screening process is called "affinity maturation".
Image source: In the process of 123RF affinity maturation, the decisive factor that B cells with different affinities must compete for is the help signal of T cells.
Through direct contact with B cells, T cells transmit these help signals that allow B cells to survive and clone proliferation.
The higher the affinity of B cells, the more help signals they can get when they come into contact with T cells, the better their survival, the more proliferation, and the easier it is to differentiate into plasma cells.
However, due to various reasons, each contact between T cells and B cells in the germinal center is very short.
As a result, even high-affinity B cells need to contact multiple T cells continuously to obtain sufficient help signals to complete the positive direction.
filter.
There are many B cells and few T cells in the germinal center, and these cells are constantly moving.
The probability of effective collision between high-affinity B cells and T cells directly affects the efficiency of affinity maturation.
So, is the encounter of T cells and B cells completely random? The process of affinity maturation can certainly be carried out under completely random encounters, but the efficiency may not be high.
Researchers in the Qihai group speculated that there may be a mechanism that selectively promotes the collision of T cells and high-affinity B cells, thereby increasing the efficiency of antibody affinity maturation.
Interestingly, if this hypothesis is true, a direct theoretical derivation is that T cells should obtain information about the affinity of B cells before they collide with B cells.
However, this deduced prediction is counterintuitive, because T cells can "learn" the affinity of B cells by experiencing the amount of antigen presented by B cells only after they are in contact with B cells.
The immune system uses protein signaling molecules called chemokines to control the directional movement of lymphocytes to achieve cell recruitment.
The researchers of the Qi Hai group therefore speculate that perhaps high-affinity B cells may express a certain chemokine through a certain mechanism to enhance the ability to recruit T cells; in this way, T cells may sense and chemoat at a distance.
Selectively chase high-affinity B cells to promote efficient screening of plasma cells that secrete high-affinity antibodies.
In order to test this hypothesis, the researchers first screened all chemokines and found that germinal center B cells significantly up-regulate the expression of chemokine CCL22 after receiving T cell help signals; germinal center T cells express CCL22 receptor CCR4 .
Through the two-photon intravital microscopy imaging technology, the researchers found that whether it is the absence of CCR4 in T cells or the absence of CCL22 and CCL17 in B cells (the sister chemokine of CCL22, which also acts on CCR4), the collision probability of T and B cells will be significantly reduced.
, Which shows that chemotaxis indeed promotes the interaction between cells in the germinal center.
Furthermore, by comparing the expression of chemokines of different affinity B cells and analyzing CCL22 gene reporter mice, the researchers confirmed that high-affinity B cells in the germinal center express more CCL22, and CCL22 can also indicate high-affinity B cells.
In the body, allowing B cells to receive more help signals from T cells in a short period of time can quickly increase the expression of CCL22; if the help signals from T cells are blocked quickly, the expression of CCL22 can be quickly reduced.
It can be seen from this that CCL22 is a factor that is affinity-coupled with B cell antibodies.
As a marker, it can transmit B cell affinity information to distant T cells.
At the same time, it also establishes a positive feedback loop with T cell help signals.
This positive feedback between cells allows T cells to patronize more high-affinity B cells, which makes it easier to obtain more help signals, and more help signals make these high-affinity cells express more CCL22 and further recruit T cells ( Schematic).
Affinity-coupled CCL22 promotes the positive selection of germinal centers: the help signal of T cells (contact dependence, affinity coupling) makes B cells up-regulate CCL22, and CCL22 enables this B cell to recruit more T cells to patronize, making it more likely Get more help signals from T cells, and more help signals make these high-affinity cells express more CCL22, and further recruit T cells.
This positive feedback loop promotes the screening of high-affinity antibodies.
The researchers of the Qihai group have further confirmed two important inferences of this positive feedback model through immunization experiments: 1.
When all B cells cannot produce the chemokines CCL22 and CCL17, the affinity maturation process will slow down; 2.
Forced to compete and be screened in the same germinal center with wild-type cells, B cells that cannot express CCL22 and CCL17 will suffer stronger selective pressure due to their lack of the ability to recruit T cells to help, and cannot effectively participate in the production of plasma cells that secrete antibodies.
process.
Finally, the Qihai group researchers also found that human tonsil germinal center T cells also express chemokine receptor CCR4, germinal center B cells also upregulate chemokine CCL22 in response to T cell help signals, and those germinal centers that express CCL22 B cells are enriched and express many genes that T cell help signals will up-regulate, suggesting that a similar mechanism is working in the life center.
Based on this, the Qihai group researchers revealed a new mechanism that promotes the maturation of germinal center antibody affinity mediated by the chemokine CCL22.
Using the principle that secreted chemokines can act at a certain distance, the immune system cleverly transforms the affinity information that can only be transmitted through the direct contact of T and B cells into information that can be obtained at a certain distance.
Thus, the limited T cells can be more effectively focused on the B cells whose affinity is most likely to be increased, and the affinity maturation is promoted.
Revealing this new mechanism may provide new ideas for antibody vaccine design.
▲The corresponding author of this study, Professor Qi Hai from the Institute of Immunology, Tsinghua University, is the winner of the 2017 WuXi AppTec Life Chemistry Research Award "Scholar Award" (Image source: WuXi AppTec) Professor Qi Hai's research group has been committed to it for a long time He studied the regulation mechanism of antibody response and germinal center response, and published a series of original papers in journals such as "Nature" and "Science" on cutting-edge scientific issues in this field.
Tsinghua University School of Medicine 2015 doctoral student Bo Liu is the first author of this article.
The 2017 doctoral student Lin Yihan and the graduated Dr.
Yan Jiacong, Dr.
Liu Dan, and Dr.
Ma Weiwei have made important contributions.
This project has received indispensable cooperation and support from many parties, including Professor Liu Wanli, Professor Wang Jianbin and Dr.
Yao Jiacheng from the School of Life Sciences of Tsinghua University, and Professor Zhang Luo and Professor Wang Chengshuo from Beijing Tongren Hospital of Capital Medical University. Funding for this project comes from the National Key R&D Project Program of the Ministry of Science and Technology (Project 2018YFE0200300), the National Natural Science Foundation of China (Projects 81621002, 31830023 and 81761128019), Tsinghua-Peking University Life Sciences Joint Center, Beijing Municipal Commission of Science and Technology, Beijing Frontiers of Biological Structure Research center.
Original link: https:// Long press the QR code to follow us
Nature published an online publication of Professor Qi Hai’s research group from the Institute of Immunology of Tsinghua University entitled Affinity-coupled CCL22 promotes positive selection in germinal centres ("Affinity-coupled CCL22 promotes positive selection in germinal centres" CCL22 promotes forward screening of germinal centers") research paper.
The study found that in the antibody immune response, the chemokine CCL22 promotes a new mechanism for the production of high-affinity antibodies, which provides a potential new target for future improved vaccine development.
Antibodies are an important immune mechanism for the body to resist the invasion of viruses, bacteria and other pathogens.
Vaccines that induce protective antibodies are an important weapon to curb the spread of many pathogens, including the new coronavirus.
Protective antibodies not only need to specifically recognize the pathogen (antigen), but also need to bind to the antigen tightly (high affinity) in order to block the infection of cells and tissues by the pathogen.
Antibodies are produced by B cells, but there are only a few B cells that can produce high-affinity antibodies; they occur in lymphoid tissues called "germinal centers", and are selected from many B cells with different affinities through a Darwinian evolutionary screening process Selected from among them, and then differentiated into plasma cells (B cells that continuously secrete antibodies).
This Darwinian evolutionary screening process is called "affinity maturation".
Image source: In the process of 123RF affinity maturation, the decisive factor that B cells with different affinities must compete for is the help signal of T cells.
Through direct contact with B cells, T cells transmit these help signals that allow B cells to survive and clone proliferation.
The higher the affinity of B cells, the more help signals they can get when they come into contact with T cells, the better their survival, the more proliferation, and the easier it is to differentiate into plasma cells.
However, due to various reasons, each contact between T cells and B cells in the germinal center is very short.
As a result, even high-affinity B cells need to contact multiple T cells continuously to obtain sufficient help signals to complete the positive direction.
filter.
There are many B cells and few T cells in the germinal center, and these cells are constantly moving.
The probability of effective collision between high-affinity B cells and T cells directly affects the efficiency of affinity maturation.
So, is the encounter of T cells and B cells completely random? The process of affinity maturation can certainly be carried out under completely random encounters, but the efficiency may not be high.
Researchers in the Qihai group speculated that there may be a mechanism that selectively promotes the collision of T cells and high-affinity B cells, thereby increasing the efficiency of antibody affinity maturation.
Interestingly, if this hypothesis is true, a direct theoretical derivation is that T cells should obtain information about the affinity of B cells before they collide with B cells.
However, this deduced prediction is counterintuitive, because T cells can "learn" the affinity of B cells by experiencing the amount of antigen presented by B cells only after they are in contact with B cells.
The immune system uses protein signaling molecules called chemokines to control the directional movement of lymphocytes to achieve cell recruitment.
The researchers of the Qi Hai group therefore speculate that perhaps high-affinity B cells may express a certain chemokine through a certain mechanism to enhance the ability to recruit T cells; in this way, T cells may sense and chemoat at a distance.
Selectively chase high-affinity B cells to promote efficient screening of plasma cells that secrete high-affinity antibodies.
In order to test this hypothesis, the researchers first screened all chemokines and found that germinal center B cells significantly up-regulate the expression of chemokine CCL22 after receiving T cell help signals; germinal center T cells express CCL22 receptor CCR4 .
Through the two-photon intravital microscopy imaging technology, the researchers found that whether it is the absence of CCR4 in T cells or the absence of CCL22 and CCL17 in B cells (the sister chemokine of CCL22, which also acts on CCR4), the collision probability of T and B cells will be significantly reduced.
, Which shows that chemotaxis indeed promotes the interaction between cells in the germinal center.
Furthermore, by comparing the expression of chemokines of different affinity B cells and analyzing CCL22 gene reporter mice, the researchers confirmed that high-affinity B cells in the germinal center express more CCL22, and CCL22 can also indicate high-affinity B cells.
In the body, allowing B cells to receive more help signals from T cells in a short period of time can quickly increase the expression of CCL22; if the help signals from T cells are blocked quickly, the expression of CCL22 can be quickly reduced.
It can be seen from this that CCL22 is a factor that is affinity-coupled with B cell antibodies.
As a marker, it can transmit B cell affinity information to distant T cells.
At the same time, it also establishes a positive feedback loop with T cell help signals.
This positive feedback between cells allows T cells to patronize more high-affinity B cells, which makes it easier to obtain more help signals, and more help signals make these high-affinity cells express more CCL22 and further recruit T cells ( Schematic).
Affinity-coupled CCL22 promotes the positive selection of germinal centers: the help signal of T cells (contact dependence, affinity coupling) makes B cells up-regulate CCL22, and CCL22 enables this B cell to recruit more T cells to patronize, making it more likely Get more help signals from T cells, and more help signals make these high-affinity cells express more CCL22, and further recruit T cells.
This positive feedback loop promotes the screening of high-affinity antibodies.
The researchers of the Qihai group have further confirmed two important inferences of this positive feedback model through immunization experiments: 1.
When all B cells cannot produce the chemokines CCL22 and CCL17, the affinity maturation process will slow down; 2.
Forced to compete and be screened in the same germinal center with wild-type cells, B cells that cannot express CCL22 and CCL17 will suffer stronger selective pressure due to their lack of the ability to recruit T cells to help, and cannot effectively participate in the production of plasma cells that secrete antibodies.
process.
Finally, the Qihai group researchers also found that human tonsil germinal center T cells also express chemokine receptor CCR4, germinal center B cells also upregulate chemokine CCL22 in response to T cell help signals, and those germinal centers that express CCL22 B cells are enriched and express many genes that T cell help signals will up-regulate, suggesting that a similar mechanism is working in the life center.
Based on this, the Qihai group researchers revealed a new mechanism that promotes the maturation of germinal center antibody affinity mediated by the chemokine CCL22.
Using the principle that secreted chemokines can act at a certain distance, the immune system cleverly transforms the affinity information that can only be transmitted through the direct contact of T and B cells into information that can be obtained at a certain distance.
Thus, the limited T cells can be more effectively focused on the B cells whose affinity is most likely to be increased, and the affinity maturation is promoted.
Revealing this new mechanism may provide new ideas for antibody vaccine design.
▲The corresponding author of this study, Professor Qi Hai from the Institute of Immunology, Tsinghua University, is the winner of the 2017 WuXi AppTec Life Chemistry Research Award "Scholar Award" (Image source: WuXi AppTec) Professor Qi Hai's research group has been committed to it for a long time He studied the regulation mechanism of antibody response and germinal center response, and published a series of original papers in journals such as "Nature" and "Science" on cutting-edge scientific issues in this field.
Tsinghua University School of Medicine 2015 doctoral student Bo Liu is the first author of this article.
The 2017 doctoral student Lin Yihan and the graduated Dr.
Yan Jiacong, Dr.
Liu Dan, and Dr.
Ma Weiwei have made important contributions.
This project has received indispensable cooperation and support from many parties, including Professor Liu Wanli, Professor Wang Jianbin and Dr.
Yao Jiacheng from the School of Life Sciences of Tsinghua University, and Professor Zhang Luo and Professor Wang Chengshuo from Beijing Tongren Hospital of Capital Medical University. Funding for this project comes from the National Key R&D Project Program of the Ministry of Science and Technology (Project 2018YFE0200300), the National Natural Science Foundation of China (Projects 81621002, 31830023 and 81761128019), Tsinghua-Peking University Life Sciences Joint Center, Beijing Municipal Commission of Science and Technology, Beijing Frontiers of Biological Structure Research center.
Original link: https:// Long press the QR code to follow us
