The mouse genome has a high degree of homology with the human genome,and its physiological,biochemical,and developmental regulation mechanisms are similar to those of humans;therefore,mice are widely used as experimen...The mouse genome has a high degree of homology with the human genome,and its physiological,biochemical,and developmental regulation mechanisms are similar to those of humans;therefore,mice are widely used as experimental animals.However,it is undeniable that interspecies differences between humans and mice can lead to experimental errors.The differences in the immune system have become an impor-tant factor limiting current immunological research.The application of immunodefi-cient mice provides a possible solution to these problems.By transplanting human immune cells or tissues,such as peripheral blood mononuclear cells or hematopoietic stem cells,into immunodeficient mice,a human immune system can be reconstituted in the mouse body,and the engrafted immune cells can elicit human-specific immune responses.Researchers have been actively exploring the development and differen-tiation conditions of host recipient animals and grafts in order to achieve better im-mune reconstitution.Through genetic engineering methods,immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts.From initially only being able to reconstruct single T lymphocyte lineages,it is now possible to reconstruct lymphoid and myeloid cells,providing important research tools for immunology-related studies.In this review,we compare the differences in immune systems of humans and mice,describe the devel-opment history of human immune reconstitution from the perspectives of immuno-deficient mice and grafts,and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution,aiming to provide important references for im-munological related researches.展开更多
COVID‐19 patients can develop clinical and histopathological features associated with fibrosis,but the pathogenesis of fibrosis remains poorly understood.CD147 has been identified as a universal receptor for SARS-CoV...COVID‐19 patients can develop clinical and histopathological features associated with fibrosis,but the pathogenesis of fibrosis remains poorly understood.CD147 has been identified as a universal receptor for SARS-CoV-2 and its variants,which could initiate COVID-19-related cytokine storm.Here,we systemically analyzed lung pathogenesis in SARS-CoV-2-and its delta variant-infected humanized CD147 transgenic mice.Histopathology and Transmission Electron Microscopy revealed inflammation,fibroblast expansion and pronounced fibrotic remodeling in SARS-CoV-2-infected lungs.Consistently,RNA-sequencing identified a set of fibrosis signature genes.Furthermore,we identified CD147 as a crucial regulator for fibroblast activation induced by SARS-CoV-2.We found conditional knockout of CD147 in fibroblast suppressed activation of fibroblasts,decreasing susceptibility to bleomycin-induced pulmonary fibrosis.Meplazumab,a CD147 antibody,was able to inhibit the accumulation of activated fibroblasts and the production of ECM proteins,thus alleviating the progression of pulmonary fibrosis caused by SARS-CoV-2.In conclusion,we demonstrated that CD147 contributed to SARS-CoV-2-triggered progressive pulmonary fibrosis and identified CD147 as a potential therapeutic target for treating patients with post-COVID-19 pulmonary fibrosis.展开更多
Regulatory T cell(Treg)stability is necessary for the proper control of immune activity and tissue homeostasis.However,it remains unclear whether Treg stability must be continually reinforced or is established during ...Regulatory T cell(Treg)stability is necessary for the proper control of immune activity and tissue homeostasis.However,it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions.Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability.Here,we demonstrate that to maintain Foxp3 protein expression,Tregs require cell-to-cell contact,which is mediated by the CD147-CD98 interaction.As Tregs are produced,CD147,which is expressed on their surface,is stimulated by CD98,which is widely expressed in the physiological environment.As a result,CD147’s intracellular domain binds to CDK2 and retains it near the membrane,leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation.In addition,the optimal distribution of Foxp3+Tregs under both pathological and physiological conditions depends on CD98 expression.Thus,our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment.More importantly,Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability,which has guiding significance for the application of Tregs in immunotherapy.展开更多
Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity.Here,we show that the loss of CD147 on T cells prevents thymic senescence,resulting in slowed shrinkage of the thymus...Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity.Here,we show that the loss of CD147 on T cells prevents thymic senescence,resulting in slowed shrinkage of the thymus with age and increased production of naive T cells.This phenotype is the result of slowing of the epithelial-mesenchymal transition(EMT)process in thymic epithelial cells(TECs),which eventually leads to reduced adipocyte accumulation.In an in vitro coculture system,we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-5mad2/FoxC2 signaling.Moreover,CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs.In the presence of TGFβ,Annexin A2 and E-cadherin colocalize on TECs.However,CD147 on T cells competitively binds to Annexin A2 on TECs,leading to the isolation of E-cadherin.Then,the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase,the phosphorylation of which was induced by TGFβ,and finally,p-E-cadherin is degraded.Thus,in the thymus,the interaction between T ceils and TECs contributes to thymic involution with age.In this study,we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFβ and/or CD147 may serve as a strategy to hinder age-related thymic involution.展开更多
基金Scientific and Technological Resources Coordination Project of Shaanxi Province,Grant/Award Number:2020PT-002,2022PT-43 and CX-PT-18Special Fund for Military Laboratory Animals,Grant/Award Number:SYDW_KY(2021)13State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers,Grant/Award Number:CBSKL2022ZZ28。
文摘The mouse genome has a high degree of homology with the human genome,and its physiological,biochemical,and developmental regulation mechanisms are similar to those of humans;therefore,mice are widely used as experimental animals.However,it is undeniable that interspecies differences between humans and mice can lead to experimental errors.The differences in the immune system have become an impor-tant factor limiting current immunological research.The application of immunodefi-cient mice provides a possible solution to these problems.By transplanting human immune cells or tissues,such as peripheral blood mononuclear cells or hematopoietic stem cells,into immunodeficient mice,a human immune system can be reconstituted in the mouse body,and the engrafted immune cells can elicit human-specific immune responses.Researchers have been actively exploring the development and differen-tiation conditions of host recipient animals and grafts in order to achieve better im-mune reconstitution.Through genetic engineering methods,immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts.From initially only being able to reconstruct single T lymphocyte lineages,it is now possible to reconstruct lymphoid and myeloid cells,providing important research tools for immunology-related studies.In this review,we compare the differences in immune systems of humans and mice,describe the devel-opment history of human immune reconstitution from the perspectives of immuno-deficient mice and grafts,and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution,aiming to provide important references for im-munological related researches.
基金National Natural Science Foundation of China(92169211,82022059)National Natural Science Fund for Excellent Young Scientists Fund Program(Overseas)+1 种基金Key R&D Plan Projects in Shaanxi Province(2020ZDXM2-SF-01)Young Elite Scientist Sponsorship Program by Cast of China Association for Science and Technology(YESS20200011).
文摘COVID‐19 patients can develop clinical and histopathological features associated with fibrosis,but the pathogenesis of fibrosis remains poorly understood.CD147 has been identified as a universal receptor for SARS-CoV-2 and its variants,which could initiate COVID-19-related cytokine storm.Here,we systemically analyzed lung pathogenesis in SARS-CoV-2-and its delta variant-infected humanized CD147 transgenic mice.Histopathology and Transmission Electron Microscopy revealed inflammation,fibroblast expansion and pronounced fibrotic remodeling in SARS-CoV-2-infected lungs.Consistently,RNA-sequencing identified a set of fibrosis signature genes.Furthermore,we identified CD147 as a crucial regulator for fibroblast activation induced by SARS-CoV-2.We found conditional knockout of CD147 in fibroblast suppressed activation of fibroblasts,decreasing susceptibility to bleomycin-induced pulmonary fibrosis.Meplazumab,a CD147 antibody,was able to inhibit the accumulation of activated fibroblasts and the production of ECM proteins,thus alleviating the progression of pulmonary fibrosis caused by SARS-CoV-2.In conclusion,we demonstrated that CD147 contributed to SARS-CoV-2-triggered progressive pulmonary fibrosis and identified CD147 as a potential therapeutic target for treating patients with post-COVID-19 pulmonary fibrosis.
基金This work was supported by the National Natural Science Foundation of China(31800756)the Science and Technology Plan of Shaanxi Province(2020SF-211).
文摘Regulatory T cell(Treg)stability is necessary for the proper control of immune activity and tissue homeostasis.However,it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions.Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability.Here,we demonstrate that to maintain Foxp3 protein expression,Tregs require cell-to-cell contact,which is mediated by the CD147-CD98 interaction.As Tregs are produced,CD147,which is expressed on their surface,is stimulated by CD98,which is widely expressed in the physiological environment.As a result,CD147’s intracellular domain binds to CDK2 and retains it near the membrane,leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation.In addition,the optimal distribution of Foxp3+Tregs under both pathological and physiological conditions depends on CD98 expression.Thus,our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment.More importantly,Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability,which has guiding significance for the application of Tregs in immunotherapy.
基金supported by grants from the National Key Research and Development Program of China(2018YFA0109000)National Natural Science Foundation of China(31800756).
文摘Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity.Here,we show that the loss of CD147 on T cells prevents thymic senescence,resulting in slowed shrinkage of the thymus with age and increased production of naive T cells.This phenotype is the result of slowing of the epithelial-mesenchymal transition(EMT)process in thymic epithelial cells(TECs),which eventually leads to reduced adipocyte accumulation.In an in vitro coculture system,we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-5mad2/FoxC2 signaling.Moreover,CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs.In the presence of TGFβ,Annexin A2 and E-cadherin colocalize on TECs.However,CD147 on T cells competitively binds to Annexin A2 on TECs,leading to the isolation of E-cadherin.Then,the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase,the phosphorylation of which was induced by TGFβ,and finally,p-E-cadherin is degraded.Thus,in the thymus,the interaction between T ceils and TECs contributes to thymic involution with age.In this study,we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFβ and/or CD147 may serve as a strategy to hinder age-related thymic involution.
