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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNatureT follicular helper (Tfh) cells play an important role in regulating humoral immunity, especially the germinal center response
.
However, how CD4+ T cells integrate antigen and costimulatory signals during Tfh cell development is still poorly understood
.
On October 12, 2021, Tsinghua University’s Dong Chen team published a research paper entitled "Costimulation molecules differentially regulate the ERK-Zfp831 axis to shape T follicular helper cell differentiation" in Immunity.
The study found that phorbol 12-nutmeg Ester 13-acetate (PMA) + ionomycin (P+I) stimulation combined with interleukin 6 (IL-6) effectively induces Tfh cell-like transcriptome programs in vitro
.
The ERK kinase pathway is weakened by P+I stimulation; ERK2 inhibition enhances the development of Tfh cells in vitro and in vivo
.
The study observed that inducible T cell costimulator (ICOS), but not CD28, lacks the ability to activate ERK, which is important for maintaining Tfh cell development
.
The expression of transcription factor Zfp831 is inhibited by ERK, which promotes Tfh cell differentiation by directly up-regulating the expression of transcription factors Bcl6 and Tcf7
.
Therefore, this study determined that the ERK-Zfp831 axis, which is regulated by costimulatory signals, plays a key regulatory role in Tfh cell development
.
In the immune response, T cells provide help for B cells, contributing to survival, proliferation, class switching, and affinity maturation
.
CD4+ T follicular helper (Tfh) cells expressing CXCR5 are located in the germinal center and are first hypothesized to be a subset of helper T cells, and then the expression of Bcl6 is defined as their lineage-specific transcription factor (TF)
.
Tfh cells are necessary for humoral immunity against various pathogens
.
In the lymphocytic choriomeningitis virus (LCMV) model, Tfh cells help control chronic viral infections by promoting the production of neutralizing antibodies
.
By regulating antibody production and B cell memory formation, Tfh cells are also essential in the immune response to influenza vaccine
.
Excessive Tfh cell response may lead to autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatic diseases
.
The development and function of Tfh cells have been shown to be regulated by various TFs
.
Although Bcl6 is a lineage-specific TF in the response of Tfh cells, its function is inhibited by TF Blimp1.
The Bcl6-Blimp1 axis determines the bifurcation point of Tfh and non-Tfh cell development
.
TF Ascl2, but not Bcl6, induces Cxcr5 chemokine receptor expression and plays an important role in early Tfh cell migration
.
At the same time, T cell antigen receptor (TcR) signals regulate Tfh cell differentiation through TFs, BATF and IRF4
.
BATF acts as a multifunctional TF in the process of T cell polarization.
By inducing the expression of Bcl6 and Rorc, it is necessary for the generation of Tfh and T helper-17 (Th17) cells
.
Irf4-/- CD4+ T cells cannot produce Tfh cells in the body
.
Article pattern (picture from Immunity) In addition, interleukin (IL)-6-STAT3 is essential for initiating Tfh cell development
.
Tox2 is a TF downstream of IL-6 and can promote the expression of Bcl6 and Cxcr5
.
Tfh cells selectively express TF TCF1, which upregulates the expression of Bcl6 in the LCMV infection model
.
At the same time, TF Foxo1 and Bach2 directly inhibit Bcl6 expression and limit the formation of Tfh cells
.
All these TFs form a network that can finely regulate the differentiation of Tfh cells
.
The differentiation of CD4+ T cells is controlled by cytokines
.
IL-6 and IL-21 have previously been reported to be important in the production of Tfh cells
.
On the contrary, IL-2 and IL-7 can effectively inhibit the development of Tfh cells
.
In addition, it is reported that IL-27, which shares the gp130 co-receptor subunit with IL-6, can induce IL-21 expression in Tfh cells, thereby promoting their differentiation
.
TcR and costimulation are also important in T cell differentiation
.
It has been reported that weak TcR strength is beneficial to Tfh cell production, but this view has been challenged by others
.
A recent report showed that weak TcR signals promote Tfh cell differentiation
.
Tfh cell differentiation requires inducible T cell costimulatory factor (ICOS), which belongs to the CD28 costimulatory family
.
CD28 and ICOS differentially regulate Tfh cell development: CD28 is important for the early stages of Tfh cell development, and ICOS is necessary to maintain Tfh cell development
.
CD28 and ICOS share a common downstream PI3K signaling pathway
.
PI3K activation in Tfh cells mediates the expression and correct localization of CXCR5
.
ICOS activation of PI3K has been shown to be necessary to support the development of Tfh cells
.
In addition, it has been found that the IProx motif in ICOS specifically recruits TBK1 kinase, which is required for Tfh cell production
.
On the other hand, growth factor receptor binding protein 2 (Grb2) can be recruited by CD28, but not ICOS, to activate the ERK pathway
.
Replacing the intracellular domain of CD28 with the intracellular domain of ICOS in the chimeric antigen receptor (CAR) impairs its ability to activate the ERK pathway; however, it is not clear whether this differential effect will affect T cell differentiation
.
In this study, the signal mechanism in the differentiation process of Tfh cells was explored
.
This study shows that ERK negatively regulates Tfh cell differentiation
.
ICOS cannot activate ERK like CD28, which is important in the production of Tfh cells
.
The study also discovered a TF Zfp831 that is negatively regulated by the ERK pathway, which directly binds to key Tfh cell characteristic genes and plays a role in regulating the differentiation of Tfh cells
.
Therefore, this study reveals the signaling mechanism of Tfh cell development, which has an impact on autoimmune diseases
.
Reference message: https://#%20
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNatureT follicular helper (Tfh) cells play an important role in regulating humoral immunity, especially the germinal center response
.
However, how CD4+ T cells integrate antigen and costimulatory signals during Tfh cell development is still poorly understood
.
On October 12, 2021, Tsinghua University’s Dong Chen team published a research paper entitled "Costimulation molecules differentially regulate the ERK-Zfp831 axis to shape T follicular helper cell differentiation" in Immunity.
The study found that phorbol 12-nutmeg Ester 13-acetate (PMA) + ionomycin (P+I) stimulation combined with interleukin 6 (IL-6) effectively induces Tfh cell-like transcriptome programs in vitro
.
The ERK kinase pathway is weakened by P+I stimulation; ERK2 inhibition enhances the development of Tfh cells in vitro and in vivo
.
The study observed that inducible T cell costimulator (ICOS), but not CD28, lacks the ability to activate ERK, which is important for maintaining Tfh cell development
.
The expression of transcription factor Zfp831 is inhibited by ERK, which promotes Tfh cell differentiation by directly up-regulating the expression of transcription factors Bcl6 and Tcf7
.
Therefore, this study determined that the ERK-Zfp831 axis, which is regulated by costimulatory signals, plays a key regulatory role in Tfh cell development
.
In the immune response, T cells provide help for B cells, contributing to survival, proliferation, class switching, and affinity maturation
.
CD4+ T follicular helper (Tfh) cells expressing CXCR5 are located in the germinal center and are first hypothesized to be a subset of helper T cells, and then the expression of Bcl6 is defined as their lineage-specific transcription factor (TF)
.
Tfh cells are necessary for humoral immunity against various pathogens
.
In the lymphocytic choriomeningitis virus (LCMV) model, Tfh cells help control chronic viral infections by promoting the production of neutralizing antibodies
.
By regulating antibody production and B cell memory formation, Tfh cells are also essential in the immune response to influenza vaccine
.
Excessive Tfh cell response may lead to autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatic diseases
.
The development and function of Tfh cells have been shown to be regulated by various TFs
.
Although Bcl6 is a lineage-specific TF in the response of Tfh cells, its function is inhibited by TF Blimp1.
The Bcl6-Blimp1 axis determines the bifurcation point of Tfh and non-Tfh cell development
.
TF Ascl2, but not Bcl6, induces Cxcr5 chemokine receptor expression and plays an important role in early Tfh cell migration
.
At the same time, T cell antigen receptor (TcR) signals regulate Tfh cell differentiation through TFs, BATF and IRF4
.
BATF acts as a multifunctional TF in the process of T cell polarization.
By inducing the expression of Bcl6 and Rorc, it is necessary for the generation of Tfh and T helper-17 (Th17) cells
.
Irf4-/- CD4+ T cells cannot produce Tfh cells in the body
.
Article pattern (picture from Immunity) In addition, interleukin (IL)-6-STAT3 is essential for initiating Tfh cell development
.
Tox2 is a TF downstream of IL-6 and can promote the expression of Bcl6 and Cxcr5
.
Tfh cells selectively express TF TCF1, which upregulates the expression of Bcl6 in the LCMV infection model
.
At the same time, TF Foxo1 and Bach2 directly inhibit Bcl6 expression and limit the formation of Tfh cells
.
All these TFs form a network that can finely regulate the differentiation of Tfh cells
.
The differentiation of CD4+ T cells is controlled by cytokines
.
IL-6 and IL-21 have previously been reported to be important in the production of Tfh cells
.
On the contrary, IL-2 and IL-7 can effectively inhibit the development of Tfh cells
.
In addition, it is reported that IL-27, which shares the gp130 co-receptor subunit with IL-6, can induce IL-21 expression in Tfh cells, thereby promoting their differentiation
.
TcR and costimulation are also important in T cell differentiation
.
It has been reported that weak TcR strength is beneficial to Tfh cell production, but this view has been challenged by others
.
A recent report showed that weak TcR signals promote Tfh cell differentiation
.
Tfh cell differentiation requires inducible T cell costimulatory factor (ICOS), which belongs to the CD28 costimulatory family
.
CD28 and ICOS differentially regulate Tfh cell development: CD28 is important for the early stages of Tfh cell development, and ICOS is necessary to maintain Tfh cell development
.
CD28 and ICOS share a common downstream PI3K signaling pathway
.
PI3K activation in Tfh cells mediates the expression and correct localization of CXCR5
.
ICOS activation of PI3K has been shown to be necessary to support the development of Tfh cells
.
In addition, it has been found that the IProx motif in ICOS specifically recruits TBK1 kinase, which is required for Tfh cell production
.
On the other hand, growth factor receptor binding protein 2 (Grb2) can be recruited by CD28, but not ICOS, to activate the ERK pathway
.
Replacing the intracellular domain of CD28 with the intracellular domain of ICOS in the chimeric antigen receptor (CAR) impairs its ability to activate the ERK pathway; however, it is not clear whether this differential effect will affect T cell differentiation
.
In this study, the signal mechanism in the differentiation process of Tfh cells was explored
.
This study shows that ERK negatively regulates Tfh cell differentiation
.
ICOS cannot activate ERK like CD28, which is important in the production of Tfh cells
.
The study also discovered a TF Zfp831 that is negatively regulated by the ERK pathway, which directly binds to key Tfh cell characteristic genes and plays a role in regulating the differentiation of Tfh cells
.
Therefore, this study reveals the signaling mechanism of Tfh cell development, which has an impact on autoimmune diseases
.
Reference message: https://#%20
