The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors...The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors or memory populations.However,within the tumor microenvironment(TME),metabolic stress impairs CD8+T cell anti-tumor immunity,resulting in exhausted differentiation.Recent studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy.In this review,we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions.Furthermore,we delved into the different metabolic switches that occur during T cell exhaustion,exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion,ultimately leading to a persistently exhausted state.Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.展开更多
The Sino-German Symposium on Immunology was jointly initiated by the Chinese Society of Immunology and the German Society of Immunology(DGFI)and was supported by the Sino-German Science Center of the National Natural ...The Sino-German Symposium on Immunology was jointly initiated by the Chinese Society of Immunology and the German Society of Immunology(DGFI)and was supported by the Sino-German Science Center of the National Natural Science Foundation of China.This symposium was the highest-level small-scale series forum between the two countries,and there have been eight successful sessions over the past 15 years.This series of forums promotes the continuous exchange of information and development of immunology between China and Germany through bilateral cooperation and joint training projects for young scholars.展开更多
CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchest...CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins.Here,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T cells.Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors.Mechanistically,ADAM17 regulated CD8^(+)T cells through cleavage of membrane CD122.ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T cells.Intriguingly,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid tumors.Our findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.展开更多
SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regula...SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell death.Furthermore,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset.We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptorαandβchains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/−CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T cells.In addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorαchain.Altogether,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.展开更多
In a recent paper published in Nature,Guo et al.1 demonstrated that asymmetrically segregated MYC and canonical BRG1/BRM-associated factor(cBAF)at first division of activated CD8^(+)T cells cooperate to dictate T cell...In a recent paper published in Nature,Guo et al.1 demonstrated that asymmetrically segregated MYC and canonical BRG1/BRM-associated factor(cBAF)at first division of activated CD8^(+)T cells cooperate to dictate T cell fate by remodeling of epigenetics and chromatin state.Further pharmacological or genetic inhibition of cBAF in chimeric antigen receptor T(CAR-T)cells considerably promotes their anti-tumor capacity in vivo,presumably by biased memory differentiation post transfer(Fig.1).展开更多
Over 1000 cases of pediatric hepatitis of unknown etiology have been reported worldwide since the first case was reported in the UK.To date,the etiology of pediatric hepatitis remains unknown and controversial.Adenovi...Over 1000 cases of pediatric hepatitis of unknown etiology have been reported worldwide since the first case was reported in the UK.To date,the etiology of pediatric hepatitis remains unknown and controversial.Adenovirus was first suspected to be the cause as it was present in the blood samples of the majority of cases.Partial cases have also been tested positive for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)[1].However,it is still unclear how these viruses contribute to pediatric hepatitis.In the case of a pediatric patient with SARS-CoV-2 infection,the liver biopsy showed acute submassive hepatocyte necrosis,accompanied by a significant increase in T cell infiltration[2].Furthermore,CD8+T cell dominant hepatitis induced by coronavirus disease 2019(COVID-19)vaccination has also been recently reported[3].Although it is known that T cell receptors(TCRs)can discriminate between self-and non-self-antigens,it is now well-accepted that TCRs exhibit cross-reactivity toward similar and even distinct antigen peptides[4].Thus,we hypothesized that following SARS-CoV-2 infection or vaccination,T cells carrying TCRs that recognize self-antigens undergo clonal expansion,which could eventually result in the onset of autoimmune-like hepatitis(Figure 1A).展开更多
基金National Natural Science Foundation of China(Nos.81788101,82271775,and 81972875)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(Nos.2021-I2M-1-021,2021-I2M-1-061,and 2022-I2M-1-047)+1 种基金Haihe Laboratory of Cell Ecosystem Innovation Fund(No.22HHXBSS00009)Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(Nos.BK20220049 and BK20211505)
文摘The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors or memory populations.However,within the tumor microenvironment(TME),metabolic stress impairs CD8+T cell anti-tumor immunity,resulting in exhausted differentiation.Recent studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy.In this review,we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions.Furthermore,we delved into the different metabolic switches that occur during T cell exhaustion,exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion,ultimately leading to a persistently exhausted state.Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.
文摘The Sino-German Symposium on Immunology was jointly initiated by the Chinese Society of Immunology and the German Society of Immunology(DGFI)and was supported by the Sino-German Science Center of the National Natural Science Foundation of China.This symposium was the highest-level small-scale series forum between the two countries,and there have been eight successful sessions over the past 15 years.This series of forums promotes the continuous exchange of information and development of immunology between China and Germany through bilateral cooperation and joint training projects for young scholars.
基金supported by grants from the National Key Research and Development Program of China 2021YFA1100702(to B.Z.)National Natural Science Foundation of China grants 82271792(to L.S.),32200727(to L.S.)and 82071828(to C.S.)+5 种基金Innovation Capability Support Program of Shaanxi Province 2024CX-GXPT-45(to C.S.)Natural Science Foundation of Shaanxi Province 2017JM8148(to Lin Shi)Fundamental Research Funds for the Central Universities xtr072022002(to B.Z.)the National Natural Science Foundation of China 82350114(to L.Z.)the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province BK20220049(to L.Z.)Suzhou Municipal Key Laboratory SZS2023005(to L.Z.).
文摘CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins.Here,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T cells.Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors.Mechanistically,ADAM17 regulated CD8^(+)T cells through cleavage of membrane CD122.ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T cells.Intriguingly,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid tumors.Our findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.
基金supported by the National Key R&D Program of China(2022YFA0807300)the National Natural Science Foundation of China(82271775 and 81971466)+1 种基金the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(BK20220049)and the CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-061,2021-I2M-1-047 and 2022-I2M-2-004).BZ was in part supported by the Innovation Capability Support Program of Shaanxi 2021TD-38.JZ was in part supported by a Translational Research Grant of NCRCH(2020ZKZC04)and the National Natural Science Foundation of China(82071765)supported by the Natural Science Foundation of China(NSFC 31900645).We thank Prof.Yonghong Wan from McMaster University,Canada,for his critical reading of the manuscript and helpful discussions.
文摘SEL1L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell death.Furthermore,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset.We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptorαandβchains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/−CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1l−/−CD8+T cells.In addition,IRE1αdeficiency decreased mTORC1 signaling in Sel1l−/−naïve CD8+T cells by downregulating the IL-15 receptorαchain.Altogether,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.
基金supported by the National Natural Science Foundation of China(81971466,32100724)the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(BK20220049)+1 种基金PUMC Fundamental Research Funds for the Central Universities(3332021073)CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-047,CIFMS 2021-I2M-1-061).
文摘In a recent paper published in Nature,Guo et al.1 demonstrated that asymmetrically segregated MYC and canonical BRG1/BRM-associated factor(cBAF)at first division of activated CD8^(+)T cells cooperate to dictate T cell fate by remodeling of epigenetics and chromatin state.Further pharmacological or genetic inhibition of cBAF in chimeric antigen receptor T(CAR-T)cells considerably promotes their anti-tumor capacity in vivo,presumably by biased memory differentiation post transfer(Fig.1).
基金supported by grants from the National Natural Science Foundation of China(81972875 and 32270994)the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(BK20211505)+4 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2021-RC310-014 and 2019PT310028)the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-047,2021-I2M-1-061 and 2022-I2M-2-004)the Suzhou Municipal Key Laboratory(SZS2023005)to G.L.,(2022-I2M-1-021)to Y.L.Science Fund for Creative Research Groups of the National Natural Science Foundation of China(82221004)to J.W.NCTIB Fund for R&D Platform for Cell and Gene Therapy。
文摘Over 1000 cases of pediatric hepatitis of unknown etiology have been reported worldwide since the first case was reported in the UK.To date,the etiology of pediatric hepatitis remains unknown and controversial.Adenovirus was first suspected to be the cause as it was present in the blood samples of the majority of cases.Partial cases have also been tested positive for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)[1].However,it is still unclear how these viruses contribute to pediatric hepatitis.In the case of a pediatric patient with SARS-CoV-2 infection,the liver biopsy showed acute submassive hepatocyte necrosis,accompanied by a significant increase in T cell infiltration[2].Furthermore,CD8+T cell dominant hepatitis induced by coronavirus disease 2019(COVID-19)vaccination has also been recently reported[3].Although it is known that T cell receptors(TCRs)can discriminate between self-and non-self-antigens,it is now well-accepted that TCRs exhibit cross-reactivity toward similar and even distinct antigen peptides[4].Thus,we hypothesized that following SARS-CoV-2 infection or vaccination,T cells carrying TCRs that recognize self-antigens undergo clonal expansion,which could eventually result in the onset of autoimmune-like hepatitis(Figure 1A).
