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Written | Chun Xiao Editor | Qi Nonalcoholic steatohepatitis (NASH) mainly includes obesity, insulin resistance, metabolic disorders and other features.
It is a systemic metabolic disease related to obesity, which can lead to liver disease and cancer.
T cells accompany the development of obesity and NASH, but the mechanism of T cells' liver damage to NASH is not fully understood.
On March 24, 2021, a research team led by Professor Percy A.
Knolle of Molecular Immunology at the Technical University of Munich published an article titled Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH in Nature.
In this study, the authors discovered that T cells play an indispensable role in liver immunopathology.
CD8 T cells complete auto-aggression through a series of successive activation steps.
This result provides new insights into the pathogenesis of immune-mediated metabolic diseases (such as NASH).
In this study, the authors used a preclinical mouse model of non-alcoholic fatty liver (NASH mice) fed a high-fat diet, which can be successfully modeled after 9-12 months of feeding.
In addition, liver immune cells will change [1].
NASH mice have the main characteristics of human NASH.
The author found that the liver CD8 T cells of NASH mice increased significantly.
At the same time, the liver gathered a large number of chemokine receptors CXCR6, which were co-expressed It also includes PD1, GzmB, TNF and IFNγ and apoptosis-related markers (not proliferation or survival-related markers).
This finding is slightly incompatible with the reported liver T cell classification [2, 3], so the author conducted an in-depth study.
Transcriptomics analysis of liver CXCR6+CD8 T cells found that decreased FOXO1 transcription factor activity is an important feature, which is abundant in NASH mice and NASH patients.
In terms of mechanism, liver CXCR6+CD8 T cells are derived from T cells expressing CD122.
CD122 is necessary for IL-15 signaling.
IL-15 induces FOXO1 down-regulation and CXCR6 up-regulation.
These changes together make liver CXCR6+CD8 T cells easy Affected by metabolic stimulation and trigger non-specific killing activity, the author calls this phenomenon Auto-aggression.
After overexpression of FOXO1, T cell self-attack disappeared.
Consistent with previous reports [4], short-chain fatty acid acetate further increased the expression of GzmB in CXCR6+CD8 T cells and promoted the release of TNF.
How is the self-attack of CD8 T cells achieved? Although the level of PD1 in CXCR6+CD8 T cells is very high, anti-PD1 checkpoint inhibition did not enhance self-attack, so the author began to look for ways to trigger T cell activation in a non-MHC way.
Extracellular experiments proved that by a membrane The ATP released by the channel complex PANX1 activates the self-attack of CD8 T cells, and the purinergic receptor P2RX7 is required for this process.
At the same time, with the increase of ATP, FasL is rapidly upregulated after CXCR6+CD8 T cells are exposed to ATP.
Inhibition of FasL can prevent the self-attack of CD8 T cells and improve liver damage in NASH mice.
In non-alcoholic fatty liver, the killing effect of self-aggressive CD8 T cells is essentially different from that of antigen-specific cells, which makes it a mechanism to distinguish between self-aggressive T cell immunity and protective T cell immunity.
Figure 1.
CXCR6 + CD8 T cell self-attack model in NASH.
All in all, this article found that the successive steps of mouse and human CD8 T cells to self-attack involve IL-15-driven transcriptional programming, and then through metabolic activation to perform self-attack (Figure 1).
The self-aggressiveness of CD8 T cells in the liver may be involved in the occurrence of liver cancer in NASH patients caused by chronic liver injury, and may also cause tissue damage in other organs.
The self-aggressiveness of CD8 T cells is different from the mechanism of antigen-specific killing by CD8 T cells.
This new mechanism will help future immunotherapy to avoid immune pathology while not damaging antigen-specific T cell immunity.
.
In the same period, Nature also published an article NASH limits anti-tumour surveillance in immunotherapy-treated HCC from a multi-national team in Europe.
This article echoes the activation and accumulation of CD8 T cells with high PD1 expression in the non-alcoholic fatty liver tissue in the above report through animal experiments and clinical analysis of liver cancer patients.
It also found that CD8 T cells are involved in the induction of non-alcoholic fatty liver.
Liver cancer.
Furthermore, a meta-analysis of patients with advanced liver cancer showed that immunotherapy did not significantly improve liver cancer caused by non-alcoholic fatty liver.
The author believes that the possible cause is also as stated in the previous article, the T cell in non-alcoholic fatty liver Abnormal activation leads to impaired immune surveillance.
Combining the conclusions of these two articles, stratified treatment and personalized treatment of patients with liver disease and liver cancer according to the underlying causes will greatly help the future to realize the potential of immunotherapy.
Original link: https://doi.
org/10.
1038/s41586-021-03233-8#Abs1 Reprinting instructions [Original article] BioArt original article, Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
The copyright of all published works is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
Plate maker: Qijiang Reference 1.
Wolf, MJ et al.
Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.
Cancer Cell 26, 549–564 (2014).
2 .
Fernandez-Ruiz, D.
et al.
Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.
Immunity 45, 889–902 (2016).
3.
Khan, O.
et al.
TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion.
Nature 571, 211–218 (2019).
4.
Balmer, ML et al.
Memory CD8+ T cells require increased concentrations of acetate induced by stress for optimal function.
Immunity 44, 1312–1324 ( 2016).
It is a systemic metabolic disease related to obesity, which can lead to liver disease and cancer.
T cells accompany the development of obesity and NASH, but the mechanism of T cells' liver damage to NASH is not fully understood.
On March 24, 2021, a research team led by Professor Percy A.
Knolle of Molecular Immunology at the Technical University of Munich published an article titled Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH in Nature.
In this study, the authors discovered that T cells play an indispensable role in liver immunopathology.
CD8 T cells complete auto-aggression through a series of successive activation steps.
This result provides new insights into the pathogenesis of immune-mediated metabolic diseases (such as NASH).
In this study, the authors used a preclinical mouse model of non-alcoholic fatty liver (NASH mice) fed a high-fat diet, which can be successfully modeled after 9-12 months of feeding.
In addition, liver immune cells will change [1].
NASH mice have the main characteristics of human NASH.
The author found that the liver CD8 T cells of NASH mice increased significantly.
At the same time, the liver gathered a large number of chemokine receptors CXCR6, which were co-expressed It also includes PD1, GzmB, TNF and IFNγ and apoptosis-related markers (not proliferation or survival-related markers).
This finding is slightly incompatible with the reported liver T cell classification [2, 3], so the author conducted an in-depth study.
Transcriptomics analysis of liver CXCR6+CD8 T cells found that decreased FOXO1 transcription factor activity is an important feature, which is abundant in NASH mice and NASH patients.
In terms of mechanism, liver CXCR6+CD8 T cells are derived from T cells expressing CD122.
CD122 is necessary for IL-15 signaling.
IL-15 induces FOXO1 down-regulation and CXCR6 up-regulation.
These changes together make liver CXCR6+CD8 T cells easy Affected by metabolic stimulation and trigger non-specific killing activity, the author calls this phenomenon Auto-aggression.
After overexpression of FOXO1, T cell self-attack disappeared.
Consistent with previous reports [4], short-chain fatty acid acetate further increased the expression of GzmB in CXCR6+CD8 T cells and promoted the release of TNF.
How is the self-attack of CD8 T cells achieved? Although the level of PD1 in CXCR6+CD8 T cells is very high, anti-PD1 checkpoint inhibition did not enhance self-attack, so the author began to look for ways to trigger T cell activation in a non-MHC way.
Extracellular experiments proved that by a membrane The ATP released by the channel complex PANX1 activates the self-attack of CD8 T cells, and the purinergic receptor P2RX7 is required for this process.
At the same time, with the increase of ATP, FasL is rapidly upregulated after CXCR6+CD8 T cells are exposed to ATP.
Inhibition of FasL can prevent the self-attack of CD8 T cells and improve liver damage in NASH mice.
In non-alcoholic fatty liver, the killing effect of self-aggressive CD8 T cells is essentially different from that of antigen-specific cells, which makes it a mechanism to distinguish between self-aggressive T cell immunity and protective T cell immunity.
Figure 1.
CXCR6 + CD8 T cell self-attack model in NASH.
All in all, this article found that the successive steps of mouse and human CD8 T cells to self-attack involve IL-15-driven transcriptional programming, and then through metabolic activation to perform self-attack (Figure 1).
The self-aggressiveness of CD8 T cells in the liver may be involved in the occurrence of liver cancer in NASH patients caused by chronic liver injury, and may also cause tissue damage in other organs.
The self-aggressiveness of CD8 T cells is different from the mechanism of antigen-specific killing by CD8 T cells.
This new mechanism will help future immunotherapy to avoid immune pathology while not damaging antigen-specific T cell immunity.
.
In the same period, Nature also published an article NASH limits anti-tumour surveillance in immunotherapy-treated HCC from a multi-national team in Europe.
This article echoes the activation and accumulation of CD8 T cells with high PD1 expression in the non-alcoholic fatty liver tissue in the above report through animal experiments and clinical analysis of liver cancer patients.
It also found that CD8 T cells are involved in the induction of non-alcoholic fatty liver.
Liver cancer.
Furthermore, a meta-analysis of patients with advanced liver cancer showed that immunotherapy did not significantly improve liver cancer caused by non-alcoholic fatty liver.
The author believes that the possible cause is also as stated in the previous article, the T cell in non-alcoholic fatty liver Abnormal activation leads to impaired immune surveillance.
Combining the conclusions of these two articles, stratified treatment and personalized treatment of patients with liver disease and liver cancer according to the underlying causes will greatly help the future to realize the potential of immunotherapy.
Original link: https://doi.
org/10.
1038/s41586-021-03233-8#Abs1 Reprinting instructions [Original article] BioArt original article, Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
The copyright of all published works is owned by BioArt.
BioArt reserves all statutory rights and offenders must be investigated.
Plate maker: Qijiang Reference 1.
Wolf, MJ et al.
Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.
Cancer Cell 26, 549–564 (2014).
2 .
Fernandez-Ruiz, D.
et al.
Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.
Immunity 45, 889–902 (2016).
3.
Khan, O.
et al.
TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion.
Nature 571, 211–218 (2019).
4.
Balmer, ML et al.
Memory CD8+ T cells require increased concentrations of acetate induced by stress for optimal function.
Immunity 44, 1312–1324 ( 2016).
