Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer.In addition to the common mechanisms underlying tumor recurrence,another unavoidable problem is that the...Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer.In addition to the common mechanisms underlying tumor recurrence,another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis.Transplant oncology is an emerging field that addresses oncological challenges in transplantation.In this context,a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients.Double-negative T cells(DNTs)are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor(TCR)type.Among them,TCRαβ^(+)DNTs are considered to induce immune suppression in immune-mediated diseases,while TCRγδ^(+)DNTs are widely recognized as tumor killers.As a composite cell therapy,healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host.In this work,we summarized the biological characteristics and functions of DNTs in oncology,immunology,and transplantation.Based on the multiple roles of DNTs,we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy(ACT).展开更多
Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cell...Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cells(DNT)are increasingly recognized as having critical regulatory functions in the immune system.Whether DNT expresses distinct immunoregulatory mechanisms to modulate neutrophils,as in HIRI,remains largely unknown.In this study,we found that murine and human DNT highly expressed CD39that protected DNT from extracellular ATP-induced apoptosis and generated adenosine in tandem with CD73,to induce high levels of neutrophil apoptosis.Furthermore,extracellular adenosine enhanced DNT survival and suppressive function by upregulating survivin and NKG2D expression via the A2AR/pAKT/FOXO1 signaling pathway.Adoptive transfer of DNT ameliorated HIRI in mice through the inhibition of neutrophils in a CD39-dependent manner.Lastly,the adoptive transfer of A2ar^(-/-)DNT validated the importance of adenosine/A2AR signaling,in promoting DNT survival and immunomodulatory function to protect against HIRI in vivo.In conclusion,purinergic signaling is crucial for DNT homeostasis in HIRI.Augmentation of CD39 or activation of A2AR signaling in DNT may provide novel therapeutic strategies to target innate immune disorders.展开更多
It is well known that the radiation efficiency of an acoustic dipole is very low, increasing the radiation efficiency of an acoustic dipole is a difficult task, especially in an ordinary waveguide.In addition, current...It is well known that the radiation efficiency of an acoustic dipole is very low, increasing the radiation efficiency of an acoustic dipole is a difficult task, especially in an ordinary waveguide.In addition, current acoustic superlenses all utilize in-phase sources to do the super-resolution imaging, it is almost impossible to realize super-resolution imaging of an acoustic dipole.In this paper, after using the Helmholtz resonator arrays(HRAs) which are placed at the upper and lower surfaces of the waveguide, we observe a large dipole radiation efficiency at the certain frequency, which gives a method to observe an acoustic dipole in the far field and offers a novel model which is promising to realize the superlens with a source of an acoustic dipole.We discuss how the arrangement of HRAs affects the transmission of the acoustic dipole.展开更多
T lymphocytes bearing the ab T cell receptor(TCR)but lacking CD4,CD8,and markers of natural killer(NK)cell differentiation are known as‘double-negative’(DN)T cells and have been described in both humans and rodent m...T lymphocytes bearing the ab T cell receptor(TCR)but lacking CD4,CD8,and markers of natural killer(NK)cell differentiation are known as‘double-negative’(DN)T cells and have been described in both humans and rodent models.We and others have shown that DN T cells can act as regulatory T cells(Tregs)that are able to prevent allograft rejection,graft-versus-host disease,and autoimmune diabetes.In the last few years,new data have revealed evidence of DN Treg function in vivo in rodents and humans.Moreover,significant advances have been made in the mechanisms by which DN Tregs target antigen-specific T cells.One major limitation of the field is the lack of a specific marker that can be used to distinguish truly regulatory DN T cells(DN Tregs)from non-regulatory ones,and this is the central challenge in the coming years.Here,we review recent progress on the role of DN Tregs in transplantation and autoimmunity,and their mechanisms of action.We also provide some perspectives on how DN Tregs compare with Foxp31 Tregs.展开更多
Background An increased number of double-negative T(DNT)cells expressing theαβT cell receptor(αβ+DNT cells)is one of the diagnostic criteria for autoimmune lymphoproliferative syndrome(ALPS).Moreover,these cells a...Background An increased number of double-negative T(DNT)cells expressing theαβT cell receptor(αβ+DNT cells)is one of the diagnostic criteria for autoimmune lymphoproliferative syndrome(ALPS).Moreover,these cells are expanded in a widely used murine model for lupus.However,the homeostasis ofαβ+DNT cells remains inadequately investigated in rheumatic disorders,especially in pediatric patients.Methods In this cross-sectional,prospective,and observational study,children with rheumatic disorders and healthy controls were recruited to analyze the quantity and characteristics of circulating DNT cells using fow cytometry.Results Overall,the two study groups did not difer in their total DNT cell pool in the bloodstream.However,the number ofαβ+DNT cells was signifcantly higher in rheumatic children than that in the controls,whereas theγδ+DNT cells remained similar.This expansion in the circulating pool ofαβ+DNT cells was comparable across diferent rheumatic diseases,all showing signifcant diferences from the controls in this regard.Moreover,no signifcant correlation was found betweenαβ+DNT cell numbers and disease activity.Conclusions These preliminary results indicate that circulatingαβ+DNT cells are signifcantly expanded in children with rheumatic disorders;however,this fnding appears to be a nonspecifc(disease-unrelated)marker of autoimmunity.Further and larger studies are necessary to better investigate and defne the role of DNT cells in pediatric rheumatic diseases.展开更多
基金supported by the Key Research&Development Plan of Zhejiang Province(Nos.2019C03050 and 2021C03118)the National Key Research and Development Program of China(No.2021YFA1100500)the National Natural Science Foundation of China(No.92159202)。
文摘Tumor recurrence is one of the major life-threatening complications after liver transplantation for liver cancer.In addition to the common mechanisms underlying tumor recurrence,another unavoidable problem is that the immunosuppressive therapeutic regimen after transplantation could promote tumor recurrence and metastasis.Transplant oncology is an emerging field that addresses oncological challenges in transplantation.In this context,a comprehensive therapeutic management approach is required to balance the anti-tumor treatment and immunosuppressive status of recipients.Double-negative T cells(DNTs)are a cluster of heterogeneous cells mainly consisting of two subsets stratified by T cell receptor(TCR)type.Among them,TCRαβ^(+)DNTs are considered to induce immune suppression in immune-mediated diseases,while TCRγδ^(+)DNTs are widely recognized as tumor killers.As a composite cell therapy,healthy donor-derived DNTs can be propagated to therapeutic numbers in vitro and applied for the treatment of several malignancies without impairing normal tissues or being rejected by the host.In this work,we summarized the biological characteristics and functions of DNTs in oncology,immunology,and transplantation.Based on the multiple roles of DNTs,we propose that a new balance could be achieved in liver transplant oncology using them as an off-the-shelf adoptive cell therapy(ACT).
基金supported by the grants from the National Natural Science Foundation of China(81970503,82100670,82202021and 82270606)Chinese Institutes for Medical Research+7 种基金Beijing(CX24PY16)R&D Program of Beijing Municipal Education Commission(KZ202210025036)Beijing Municipal Administration of Hospitals’Ascent Plan(DFL20220103)Beijing Nova Program(Z211100002121036)Youth Beijing Scholar(035)and the Reform and Development Program of Beijing Institute of Respiratory Medicine(Ggyfz202403)Generation of reagents and mutant mice are also supported by the National Institutes of Health(R01 DK108894R21 CA164970 and R21 CA221702)Department of Defense Award W81XWH-16-0464。
文摘Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cells(DNT)are increasingly recognized as having critical regulatory functions in the immune system.Whether DNT expresses distinct immunoregulatory mechanisms to modulate neutrophils,as in HIRI,remains largely unknown.In this study,we found that murine and human DNT highly expressed CD39that protected DNT from extracellular ATP-induced apoptosis and generated adenosine in tandem with CD73,to induce high levels of neutrophil apoptosis.Furthermore,extracellular adenosine enhanced DNT survival and suppressive function by upregulating survivin and NKG2D expression via the A2AR/pAKT/FOXO1 signaling pathway.Adoptive transfer of DNT ameliorated HIRI in mice through the inhibition of neutrophils in a CD39-dependent manner.Lastly,the adoptive transfer of A2ar^(-/-)DNT validated the importance of adenosine/A2AR signaling,in promoting DNT survival and immunomodulatory function to protect against HIRI in vivo.In conclusion,purinergic signaling is crucial for DNT homeostasis in HIRI.Augmentation of CD39 or activation of A2AR signaling in DNT may provide novel therapeutic strategies to target innate immune disorders.
基金Project supported by the National Key R&D Program of China(Grant No.2017YFA0303702)State Key Program of the National Natural Science Foundation of China(Grant No.11834008)+3 种基金the National Natural Science Foundation of China(Grant No.11774167)State Key Laboratory of Acoustics,Chinese Academy of Sciences(Grant No.SKLA201809)Key Laboratory of Underwater Acoustic Environment,Chinese Academy of Sciences(Grant No.SSHJ-KFKT-1701)AQSIQ Technology R&D Program,China(Grant No.2017QK125)
文摘It is well known that the radiation efficiency of an acoustic dipole is very low, increasing the radiation efficiency of an acoustic dipole is a difficult task, especially in an ordinary waveguide.In addition, current acoustic superlenses all utilize in-phase sources to do the super-resolution imaging, it is almost impossible to realize super-resolution imaging of an acoustic dipole.In this paper, after using the Helmholtz resonator arrays(HRAs) which are placed at the upper and lower surfaces of the waveguide, we observe a large dipole radiation efficiency at the certain frequency, which gives a method to observe an acoustic dipole in the far field and offers a novel model which is promising to realize the superlens with a source of an acoustic dipole.We discuss how the arrangement of HRAs affects the transmission of the acoustic dipole.
基金Research in our laboratory has been supported by Canadian Institutes of Health Research Grant (#14431)Canadian Cancer Society to L.Z.S.C.J.received salary support from a Terry Fox Foundation/National Cancer Institute of Canada Clinical Research Fellowship (#18014)the Clinician-Scientist Training Program,Department of Medicine,University of Toronto.
文摘T lymphocytes bearing the ab T cell receptor(TCR)but lacking CD4,CD8,and markers of natural killer(NK)cell differentiation are known as‘double-negative’(DN)T cells and have been described in both humans and rodent models.We and others have shown that DN T cells can act as regulatory T cells(Tregs)that are able to prevent allograft rejection,graft-versus-host disease,and autoimmune diabetes.In the last few years,new data have revealed evidence of DN Treg function in vivo in rodents and humans.Moreover,significant advances have been made in the mechanisms by which DN Tregs target antigen-specific T cells.One major limitation of the field is the lack of a specific marker that can be used to distinguish truly regulatory DN T cells(DN Tregs)from non-regulatory ones,and this is the central challenge in the coming years.Here,we review recent progress on the role of DN Tregs in transplantation and autoimmunity,and their mechanisms of action.We also provide some perspectives on how DN Tregs compare with Foxp31 Tregs.
基金supported by the Nazarbayev University Cooperative Research Grant 2023–2025(No.20122022CRP1604)Science Committee of the Ministry of Higher Education and Science of the Republic of Kazakhstan(Grant No.AP19677323).
文摘Background An increased number of double-negative T(DNT)cells expressing theαβT cell receptor(αβ+DNT cells)is one of the diagnostic criteria for autoimmune lymphoproliferative syndrome(ALPS).Moreover,these cells are expanded in a widely used murine model for lupus.However,the homeostasis ofαβ+DNT cells remains inadequately investigated in rheumatic disorders,especially in pediatric patients.Methods In this cross-sectional,prospective,and observational study,children with rheumatic disorders and healthy controls were recruited to analyze the quantity and characteristics of circulating DNT cells using fow cytometry.Results Overall,the two study groups did not difer in their total DNT cell pool in the bloodstream.However,the number ofαβ+DNT cells was signifcantly higher in rheumatic children than that in the controls,whereas theγδ+DNT cells remained similar.This expansion in the circulating pool ofαβ+DNT cells was comparable across diferent rheumatic diseases,all showing signifcant diferences from the controls in this regard.Moreover,no signifcant correlation was found betweenαβ+DNT cell numbers and disease activity.Conclusions These preliminary results indicate that circulatingαβ+DNT cells are signifcantly expanded in children with rheumatic disorders;however,this fnding appears to be a nonspecifc(disease-unrelated)marker of autoimmunity.Further and larger studies are necessary to better investigate and defne the role of DNT cells in pediatric rheumatic diseases.
