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Regulatory T cells (Regulatory T cells, Treg) are a special subgroup of CD4+ T cells that have a wide range of immunomodulatory and inhibitory effects
.
Since its discovery in 1995, Treg has always been a hot spot in the field of immune regulation
.
In 2003, the discovery of Foxp3, a transcription factor specifically expressed by Treg, provided a new perspective and powerful tool for Treg research
.
Foxp3 plays a vital role in the differentiation, maintenance and function of Treg
.
Because of the lack of Treg subgroups, Foxp3-deficient humans and mice will quickly develop a strong autoimmune inflammatory response after birth, which proves the indispensable role of Treg in preventing autoimmune response
.
However, if the inflammatory response has been established, whether Treg can still play a role, reverse the inflammatory response or restore immune homeostasis, is still an inconclusive and divergent question
.
Although clinical trials based on Treg cell transplantation have shown that Treg has a certain alleviating and therapeutic effect on autoimmune diseases, many studies still show that under the influence of strong immune response and related inflammatory factors in the inflammatory response microenvironment, Treg It may lose the expression of Foxp3 and lose its immunosuppressive function, which may promote immunopathology during infection
.
Existing research methods and experimental models have many limitations due to the reliance on the adoptive transfer of Treg.
Therefore, a new experimental system is urgently needed to better answer this question
.
On August 23, 2021, Alexander Y.
Rudensky's team at Memorial Sloan Kettering Cancer Center (together as Dr.
Hu Wei and Wang Zhongmin) published a titled Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity on Nature Immunology.
The paper used a new experimental method to explore the dynamics and functions of Treg in the inflammatory response
.
This study constructed a reversible Foxp3 knockout mouse model (Foxp3LSL) by adding a LoxP-Thy1.
1-Stop-LoxP transcription termination sequence before the Foxp3 coding sequence in mice
.
Foxp3LSL mice lack Tregs because they cannot express Foxp3.
They only have CD4+ T cells that should express Foxp3, but can only express the Thy1.
1 reporter gene in the termination sequence
.
These cells, called Treg wannabe by the researchers, lack immunosuppressive functions and cannot prevent autoimmune inflammation
.
When the termination sequence is removed by the inducible Cre recombinase activated by 4-hydroxy-tamoxifen, Foxp3 The expression of Treg wannabe can be specifically restored in Treg wannabe
.
The
researchers cleverly used the cytokine storm that covers Type I, II, and III inflammation caused by the lack of Foxp3 expression in the mouse to test the inflammatory environment Treg function
.
Mice have had obvious multi-organ inflammation and immunopathology two weeks after birth.
At this time, treatment of mice with 4-hydroxy-tamoxifen can restore the expression of Foxp3, and then restore in situ in multiple tissues The Treg subgroups in this mouse circumvent the disadvantages of adoptive transfer
.
Researchers have found that when reintroduced into the inflammatory response microenvironment, Treg can quickly exert an immunosuppressive function and reverse the inflammatory response in all directions
.
In just 7 days, T cell activation markers and inflammatory cytokines produced by T cells have both significantly decreased
.
In terms of humoral immunity, the restoration of Treg effectively inhibited the production of autoantibodies of IgG1, IgM, and IgE
.
Foxp3 deficiency can also cause excessive activation of innate immunity, resulting in excessive proliferation of myeloid cells and a strong acute phase response
.
The researchers found that the excessive proliferation of monocytes, neutrophils, and eosinophils, as well as the accumulation of acute phase reactive proteins in the serum, were quickly reversed by the restored Treg
.
Four weeks after Treg recovery, various inflammatory response indicators in Foxp3LSL mice, including histological analysis, were almost indistinguishable from those in healthy control mice
.
To further understand how Tregs in the inflammatory microenvironment play a role, the researchers used RNA sequencing to analyze the transcriptome of the newly recovered Tregs in Foxp3LSL mice
.
Gene expression analysis showed that compared with Tregs in healthy mice, the newly recovered Tregs showed a higher activation state and proliferation potential: these cells not only highly expressed many genes related to the immunosuppressive function of Tregs, but also up-regulated a large number of genes.
Cell cycle genes
.
The researchers guessed that Treg would be activated in the inflammatory microenvironment, speed up cell proliferation, and up-regulate immunosuppressive function, and used in vitro Treg inhibition experiments to confirm that the newly recovered Treg isolated from Foxp3LSL mice, and a healthy control group Compared with Treg isolated from mice, it has stronger immunosuppressive activity
.
The action time of 4-hydroxy-tamoxifen in mice does not exceed 72 hours.
Therefore, Foxp3LSL mice treated with a dose of 4-hydroxy-tamoxifen have only one batch at 2 weeks of age.
Treg induced within 72 hours
.
Since then, due to the loss of activity of 4-hydroxy-tamoxifen, Foxp3LSL mice will no longer have new Tregs produced by the thymus
.
This unique system allows researchers to investigate how long a single batch of Tregs that restore Foxp3 expression can maintain their function without continuous thymic output to supplement
.
Through long-term follow-up and analysis of Foxp3LSL mice, the researchers found that the batch of Tregs produced at 2 weeks of age can survive stably for a long time, and can still survive 4 months and 7 months after the expression of Foxp3 is restored.
Function normally and maintain immune homeostasis
.
The researchers used single-cell RNA sequencing to analyze the Tregs in Foxp3LSL mice that recovered Foxp3 expression for 7 months, and found that they were very similar to a type of long-term survival Treg subgroups in neonatal mice, and identified them based on transcriptome information.
A subgroup that may have a self-renewing function
.
This subgroup may play an important role in the long-term survival and maintenance of Treg in Foxp3LSL mice
.
Through the development and use of new mouse genetic tools, this study proved that Treg not only does not lose function in the inflammatory factor storm, but can accelerate cell proliferation when the inflammatory response is felt, and up-regulate immunosuppressive function to reverse inflammation Response
.
Treg can survive long-term and stably in the body and continuously maintain immune homeostasis
.
The study also gives useful enlightenment to Treg therapy, which has been highly anticipated in recent years, suggesting that Treg can control and reverse inflammation in clinical treatment, and a dose of Treg may have a long-term effect
.
Original link: https://doi.
org/10.
1038/s41590-021-01001-4 Platemaker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting without permission is prohibited.
The author has all legal rights, and offenders must be investigated
.
.
Since its discovery in 1995, Treg has always been a hot spot in the field of immune regulation
.
In 2003, the discovery of Foxp3, a transcription factor specifically expressed by Treg, provided a new perspective and powerful tool for Treg research
.
Foxp3 plays a vital role in the differentiation, maintenance and function of Treg
.
Because of the lack of Treg subgroups, Foxp3-deficient humans and mice will quickly develop a strong autoimmune inflammatory response after birth, which proves the indispensable role of Treg in preventing autoimmune response
.
However, if the inflammatory response has been established, whether Treg can still play a role, reverse the inflammatory response or restore immune homeostasis, is still an inconclusive and divergent question
.
Although clinical trials based on Treg cell transplantation have shown that Treg has a certain alleviating and therapeutic effect on autoimmune diseases, many studies still show that under the influence of strong immune response and related inflammatory factors in the inflammatory response microenvironment, Treg It may lose the expression of Foxp3 and lose its immunosuppressive function, which may promote immunopathology during infection
.
Existing research methods and experimental models have many limitations due to the reliance on the adoptive transfer of Treg.
Therefore, a new experimental system is urgently needed to better answer this question
.
On August 23, 2021, Alexander Y.
Rudensky's team at Memorial Sloan Kettering Cancer Center (together as Dr.
Hu Wei and Wang Zhongmin) published a titled Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity on Nature Immunology.
The paper used a new experimental method to explore the dynamics and functions of Treg in the inflammatory response
.
This study constructed a reversible Foxp3 knockout mouse model (Foxp3LSL) by adding a LoxP-Thy1.
1-Stop-LoxP transcription termination sequence before the Foxp3 coding sequence in mice
.
Foxp3LSL mice lack Tregs because they cannot express Foxp3.
They only have CD4+ T cells that should express Foxp3, but can only express the Thy1.
1 reporter gene in the termination sequence
.
These cells, called Treg wannabe by the researchers, lack immunosuppressive functions and cannot prevent autoimmune inflammation
.
When the termination sequence is removed by the inducible Cre recombinase activated by 4-hydroxy-tamoxifen, Foxp3 The expression of Treg wannabe can be specifically restored in Treg wannabe
.
The
researchers cleverly used the cytokine storm that covers Type I, II, and III inflammation caused by the lack of Foxp3 expression in the mouse to test the inflammatory environment Treg function
.
Mice have had obvious multi-organ inflammation and immunopathology two weeks after birth.
At this time, treatment of mice with 4-hydroxy-tamoxifen can restore the expression of Foxp3, and then restore in situ in multiple tissues The Treg subgroups in this mouse circumvent the disadvantages of adoptive transfer
.
Researchers have found that when reintroduced into the inflammatory response microenvironment, Treg can quickly exert an immunosuppressive function and reverse the inflammatory response in all directions
.
In just 7 days, T cell activation markers and inflammatory cytokines produced by T cells have both significantly decreased
.
In terms of humoral immunity, the restoration of Treg effectively inhibited the production of autoantibodies of IgG1, IgM, and IgE
.
Foxp3 deficiency can also cause excessive activation of innate immunity, resulting in excessive proliferation of myeloid cells and a strong acute phase response
.
The researchers found that the excessive proliferation of monocytes, neutrophils, and eosinophils, as well as the accumulation of acute phase reactive proteins in the serum, were quickly reversed by the restored Treg
.
Four weeks after Treg recovery, various inflammatory response indicators in Foxp3LSL mice, including histological analysis, were almost indistinguishable from those in healthy control mice
.
To further understand how Tregs in the inflammatory microenvironment play a role, the researchers used RNA sequencing to analyze the transcriptome of the newly recovered Tregs in Foxp3LSL mice
.
Gene expression analysis showed that compared with Tregs in healthy mice, the newly recovered Tregs showed a higher activation state and proliferation potential: these cells not only highly expressed many genes related to the immunosuppressive function of Tregs, but also up-regulated a large number of genes.
Cell cycle genes
.
The researchers guessed that Treg would be activated in the inflammatory microenvironment, speed up cell proliferation, and up-regulate immunosuppressive function, and used in vitro Treg inhibition experiments to confirm that the newly recovered Treg isolated from Foxp3LSL mice, and a healthy control group Compared with Treg isolated from mice, it has stronger immunosuppressive activity
.
The action time of 4-hydroxy-tamoxifen in mice does not exceed 72 hours.
Therefore, Foxp3LSL mice treated with a dose of 4-hydroxy-tamoxifen have only one batch at 2 weeks of age.
Treg induced within 72 hours
.
Since then, due to the loss of activity of 4-hydroxy-tamoxifen, Foxp3LSL mice will no longer have new Tregs produced by the thymus
.
This unique system allows researchers to investigate how long a single batch of Tregs that restore Foxp3 expression can maintain their function without continuous thymic output to supplement
.
Through long-term follow-up and analysis of Foxp3LSL mice, the researchers found that the batch of Tregs produced at 2 weeks of age can survive stably for a long time, and can still survive 4 months and 7 months after the expression of Foxp3 is restored.
Function normally and maintain immune homeostasis
.
The researchers used single-cell RNA sequencing to analyze the Tregs in Foxp3LSL mice that recovered Foxp3 expression for 7 months, and found that they were very similar to a type of long-term survival Treg subgroups in neonatal mice, and identified them based on transcriptome information.
A subgroup that may have a self-renewing function
.
This subgroup may play an important role in the long-term survival and maintenance of Treg in Foxp3LSL mice
.
Through the development and use of new mouse genetic tools, this study proved that Treg not only does not lose function in the inflammatory factor storm, but can accelerate cell proliferation when the inflammatory response is felt, and up-regulate immunosuppressive function to reverse inflammation Response
.
Treg can survive long-term and stably in the body and continuously maintain immune homeostasis
.
The study also gives useful enlightenment to Treg therapy, which has been highly anticipated in recent years, suggesting that Treg can control and reverse inflammation in clinical treatment, and a dose of Treg may have a long-term effect
.
Original link: https://doi.
org/10.
1038/s41590-021-01001-4 Platemaker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting without permission is prohibited.
The author has all legal rights, and offenders must be investigated
.
