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During the immune response process, many immune cells undergo maturation and become functionally enhanced cells, allowing them to respond to specific types of pathogens in specific ways
.
This is called "effector cell differentiation"
.
TFH cells are an important type of effector T cells discovered in recent years
.
The physiological functions of TFH cells include participating in the transmission of information in the process of B cell differentiation, assisting in activating B cells, promoting the formation of germinal centers and class switching of immunoglobulins, and maintaining long-term humoral immune responses
.
TFH cells are very important for the establishment of the immune system and the improvement of its functions, especially for the decisive regulation of humoral immunity against infectious diseases.
At the same time, it also plays an important role in related diseases such as autoimmunity and tumorigenesis
.
Although the transcription factors that regulate the differentiation of TFH cells have been extensively studied and recognized by immunologists, however, the transcriptional and post-translational mechanisms involved in the maintenance of TFH cell fate and the role of metabolic-related regulatory pathways in TFH cells have always been a blank in the field.
.
On July 7, 2021, the team of Professor Hongbo Chi from the St.
Jude Children’s Research Hospital in the United States published a research paper entitled Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine in Nature
.
This study identified the phosphatidylethanolamine (PE) synthesis pathway as a new pathway for regulating humoral immune responses
.
The study also found that different from other effector CD4+ T cell subgroups, a type of functional phospholipid-phosphatidylethanolamine is specifically distributed on the outer leaf of the cell membrane of follicular helper T cells (TFH)
.
To identify the metabolic genes that regulate the differentiation of TFH cells, the researchers established an in vivo CRISPR-Cas9 screening system targeting 3017 metabolic-related genes in the humoral immune response model induced by the LCMV-Armstrong virus strain
.
The screening results showed that the three node genes involved in the synthesis of phosphatidylethanolamine (CDP-ethanolamine pathway), Etnk1, Pcyt2 and Selenoi are all positive regulators of TFH cell differentiation
.
Subsequent verification experiments showed that CRISPR-mediated knockout of Etnk1, Pcyt2 and Selenoi genes can significantly inhibit the differentiation of TFH cells, and the degree of inhibition is equivalent to the effect of knocking out the transcription factor Bcl6 of TFH cells, which suggests that the CDP-ethanolamine pathway is the determinant in vivo The main pathway of TFH cell differentiation
.
The CDP-ethanolamine pathway is the de novo synthesis of PE in the cell.
A parallel pathway is the CDP-choline pathway, which is responsible for the synthesis of PC (phosphatidylcholine) in the cell
.
In addition, the decarboxylation process of PS (phosphatidylserine) can also produce PE
.
The authors knocked out the node genes in the CDP-choline pathway and PS decarboxylation pathway, and found that the blockade of CDP-choline pathway and PS decarboxylation pathway did not affect the differentiation of TFH cells in vivo, thus confirming that the CDP-ethanolamine pathway specifically regulates the differentiation of TFH cells
.
The researchers performed Lipidomic (phospholipid profile) analysis on different immune cells and found that compared with naïve T cells (initial T cells), the total amount of PE in TFH cells was significantly increased and TFH cells had a higher rate of PE synthesis and degradation
.
Further experiments found that unlike naïve and TH1 cells (effector T cells that can secrete IFN-γ), PE specifically distributes to the outer lobes of mouse TFH cell plasma membrane during the differentiation process of TFH cells
.
Because in most cases, intracellular PE is mainly distributed in the inner lobes of the cell membrane, the special location of PE in TFH cells further validates the key role of PE metabolism in TFH cells
.
Moreover, through the analysis of human lymph nodes and peripheral blood TFH cell subsets, the authors found that this phenotype is evolutionarily conserved, suggesting that the PE serosal distribution of TFH cells has important physiological functions
.
In terms of mechanism, the researchers found that although the differentiation of TFH cells was significantly reduced after the CDP-ethanolamine pathway was blocked, the expression level and amount of Bcl6 did not change
.
Transcriptomics analysis also further confirmed that the blockade of the CDP-ethanolamine pathway did not affect the early TFH transcription program regulated by Bcl6
.
All these indicate that the function of the CDP-ethanolamine pathway is independent of the transcription factor Bcl6 of TFH cells
.
Subsequently, the researchers observed the internalization and degradation of the chemokine receptor CXCR5 specifically expressed in TFH cells
.
At the same time, through multiple experimental methods, the researchers found that the CDP-ethanolamine pathway specifically regulates the protein expression of CXCR5 in the early stage of TFH cell differentiation, thereby driving changes in the entire TFH differentiation process
.
PE interacts with CXCR5 on the TFH cell membrane and maintains the stability of CXCR5 protein
.
Blocking the CDP-ethanolamine pathway leads to a decrease in PE levels, accelerated internalization and degradation of CXCR5, and a significant reduction in its serosal recirculation
.
Finally, by constructing T cell-specific conditional knockout mice, the researchers once again confirmed that the absence of the CDP-ethanolamine pathway significantly reduces the differentiation of TFH cells in vivo, and reduces the germinal center area of lymphoid tissues and the number of germinal center T cells homing
.
In the TFH cell differentiation model induced by antigen immunity, the lack of CDP-ethanolamine pathway severely reduces the differentiation of germinal center B cells and antibody-secreting plasma cells, and further reduces the secretion of antigen-specific antibodies (such as IgG, IgA, and IgM) , Thereby greatly weakening the body's due humoral immune response
.
In summary, this study identified a new pathway regulating the differentiation of TFH cells-CDP-ethanolamine pathway; it clarified that de novo PE synthesis signals determine the function of TFH cells and the strength of humoral immune response by regulating the location and stability of the chemokine receptor CXCR5 ; Reveal the importance of metabolic pathways and post-transcriptional regulation on the differentiation and fate of effector T cells
.
The CDP-ethanolamine pathway is a positive regulatory element for the differentiation of TFH cells, but the blocking of the CDP-choline pathway and PS decarboxylation pathway does not affect the differentiation of TFH cells, which in turn emphasizes the specificity of the CDP-ethanolamine pathway in the regulation of TFH cells
.
PE is specifically distributed in the outer lobes of the plasma membrane of TFH cells and the temporal and spatial management of the stability and localization of CXCR5 answers a long-term scientific question in the field, that is, how the dynamic expression of chemokine receptors in TFH cells is Regulated
.
Therefore, the node genes in this metabolic pathway, such as Etnk1, Pcyt2, and Selenoi, are very promising as new targets for regulating the effectiveness of vaccines and treating autoimmune diseases
.
Link to the paper: https:// Open for reprinting This article is open for reprinting: Just leave a message in this article and let us know
.
This is called "effector cell differentiation"
.
TFH cells are an important type of effector T cells discovered in recent years
.
The physiological functions of TFH cells include participating in the transmission of information in the process of B cell differentiation, assisting in activating B cells, promoting the formation of germinal centers and class switching of immunoglobulins, and maintaining long-term humoral immune responses
.
TFH cells are very important for the establishment of the immune system and the improvement of its functions, especially for the decisive regulation of humoral immunity against infectious diseases.
At the same time, it also plays an important role in related diseases such as autoimmunity and tumorigenesis
.
Although the transcription factors that regulate the differentiation of TFH cells have been extensively studied and recognized by immunologists, however, the transcriptional and post-translational mechanisms involved in the maintenance of TFH cell fate and the role of metabolic-related regulatory pathways in TFH cells have always been a blank in the field.
.
On July 7, 2021, the team of Professor Hongbo Chi from the St.
Jude Children’s Research Hospital in the United States published a research paper entitled Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine in Nature
.
This study identified the phosphatidylethanolamine (PE) synthesis pathway as a new pathway for regulating humoral immune responses
.
The study also found that different from other effector CD4+ T cell subgroups, a type of functional phospholipid-phosphatidylethanolamine is specifically distributed on the outer leaf of the cell membrane of follicular helper T cells (TFH)
.
To identify the metabolic genes that regulate the differentiation of TFH cells, the researchers established an in vivo CRISPR-Cas9 screening system targeting 3017 metabolic-related genes in the humoral immune response model induced by the LCMV-Armstrong virus strain
.
The screening results showed that the three node genes involved in the synthesis of phosphatidylethanolamine (CDP-ethanolamine pathway), Etnk1, Pcyt2 and Selenoi are all positive regulators of TFH cell differentiation
.
Subsequent verification experiments showed that CRISPR-mediated knockout of Etnk1, Pcyt2 and Selenoi genes can significantly inhibit the differentiation of TFH cells, and the degree of inhibition is equivalent to the effect of knocking out the transcription factor Bcl6 of TFH cells, which suggests that the CDP-ethanolamine pathway is the determinant in vivo The main pathway of TFH cell differentiation
.
The CDP-ethanolamine pathway is the de novo synthesis of PE in the cell.
A parallel pathway is the CDP-choline pathway, which is responsible for the synthesis of PC (phosphatidylcholine) in the cell
.
In addition, the decarboxylation process of PS (phosphatidylserine) can also produce PE
.
The authors knocked out the node genes in the CDP-choline pathway and PS decarboxylation pathway, and found that the blockade of CDP-choline pathway and PS decarboxylation pathway did not affect the differentiation of TFH cells in vivo, thus confirming that the CDP-ethanolamine pathway specifically regulates the differentiation of TFH cells
.
The researchers performed Lipidomic (phospholipid profile) analysis on different immune cells and found that compared with naïve T cells (initial T cells), the total amount of PE in TFH cells was significantly increased and TFH cells had a higher rate of PE synthesis and degradation
.
Further experiments found that unlike naïve and TH1 cells (effector T cells that can secrete IFN-γ), PE specifically distributes to the outer lobes of mouse TFH cell plasma membrane during the differentiation process of TFH cells
.
Because in most cases, intracellular PE is mainly distributed in the inner lobes of the cell membrane, the special location of PE in TFH cells further validates the key role of PE metabolism in TFH cells
.
Moreover, through the analysis of human lymph nodes and peripheral blood TFH cell subsets, the authors found that this phenotype is evolutionarily conserved, suggesting that the PE serosal distribution of TFH cells has important physiological functions
.
In terms of mechanism, the researchers found that although the differentiation of TFH cells was significantly reduced after the CDP-ethanolamine pathway was blocked, the expression level and amount of Bcl6 did not change
.
Transcriptomics analysis also further confirmed that the blockade of the CDP-ethanolamine pathway did not affect the early TFH transcription program regulated by Bcl6
.
All these indicate that the function of the CDP-ethanolamine pathway is independent of the transcription factor Bcl6 of TFH cells
.
Subsequently, the researchers observed the internalization and degradation of the chemokine receptor CXCR5 specifically expressed in TFH cells
.
At the same time, through multiple experimental methods, the researchers found that the CDP-ethanolamine pathway specifically regulates the protein expression of CXCR5 in the early stage of TFH cell differentiation, thereby driving changes in the entire TFH differentiation process
.
PE interacts with CXCR5 on the TFH cell membrane and maintains the stability of CXCR5 protein
.
Blocking the CDP-ethanolamine pathway leads to a decrease in PE levels, accelerated internalization and degradation of CXCR5, and a significant reduction in its serosal recirculation
.
Finally, by constructing T cell-specific conditional knockout mice, the researchers once again confirmed that the absence of the CDP-ethanolamine pathway significantly reduces the differentiation of TFH cells in vivo, and reduces the germinal center area of lymphoid tissues and the number of germinal center T cells homing
.
In the TFH cell differentiation model induced by antigen immunity, the lack of CDP-ethanolamine pathway severely reduces the differentiation of germinal center B cells and antibody-secreting plasma cells, and further reduces the secretion of antigen-specific antibodies (such as IgG, IgA, and IgM) , Thereby greatly weakening the body's due humoral immune response
.
In summary, this study identified a new pathway regulating the differentiation of TFH cells-CDP-ethanolamine pathway; it clarified that de novo PE synthesis signals determine the function of TFH cells and the strength of humoral immune response by regulating the location and stability of the chemokine receptor CXCR5 ; Reveal the importance of metabolic pathways and post-transcriptional regulation on the differentiation and fate of effector T cells
.
The CDP-ethanolamine pathway is a positive regulatory element for the differentiation of TFH cells, but the blocking of the CDP-choline pathway and PS decarboxylation pathway does not affect the differentiation of TFH cells, which in turn emphasizes the specificity of the CDP-ethanolamine pathway in the regulation of TFH cells
.
PE is specifically distributed in the outer lobes of the plasma membrane of TFH cells and the temporal and spatial management of the stability and localization of CXCR5 answers a long-term scientific question in the field, that is, how the dynamic expression of chemokine receptors in TFH cells is Regulated
.
Therefore, the node genes in this metabolic pathway, such as Etnk1, Pcyt2, and Selenoi, are very promising as new targets for regulating the effectiveness of vaccines and treating autoimmune diseases
.
Link to the paper: https:// Open for reprinting This article is open for reprinting: Just leave a message in this article and let us know
