Kang et al.published a research article on the treatment of ischemic stroke using engineered Treg cells(Kang et al.,Prog Biochem Biophys,2025,52(4):946-956.DOI:10.16476/j.pibb.2025.0019).Their study mainly explores th...Kang et al.published a research article on the treatment of ischemic stroke using engineered Treg cells(Kang et al.,Prog Biochem Biophys,2025,52(4):946-956.DOI:10.16476/j.pibb.2025.0019).Their study mainly explores the immunoregulatory role of regulatory T(Treg)cells in ischemic stroke,providing an innovative therapeutic strategy.Neuroinflammation is a major driver of secondary injury after stroke.Existing treatments focus on vascular recanalization while neglecting immune regulation.Their study proposes to modulate neuroinflammation through in vitro-induced Treg cells,offering a novel approach distinct from traditional thrombolysis and endovascular interventions.展开更多
OBJECTIVE Experimental autoimmune encephalomyelitis(EAE),the classical animal model for multiple sclerosis(MS)is triggered by an impaired balance of T helper(Th)cells and regulatory T(Tregs)cells.Matrine(MAT),a quinol...OBJECTIVE Experimental autoimmune encephalomyelitis(EAE),the classical animal model for multiple sclerosis(MS)is triggered by an impaired balance of T helper(Th)cells and regulatory T(Tregs)cells.Matrine(MAT),a quinolizidine alkaloid derived from the herb Radix Sophorae Flave,has been shown to ameliorate the clinical signs,inflammatory infiltration,demyelination in acute EAE rats.However,whether MAT protect from EAE by adjusting Th and Treg cells response in specific-cellular and molecular level is unknown.METHODS Herein,MAT was tested for its effects on Th1,Th2,Th17 and Treg cells in the spinal cord of EAE mice and splenocyte-extracted from EAE mice with MOG35-55-restimulated,respectively.RESULTS Our findings revealed that MAT significantly inhibit the proliferation of splenocyte,and remarkably down-regulate the differentiation of Th1/Th17 cells with decreased expressions of CD4+IFN-γ+cells and CD4+IL-17+cells in vivo and IL-17,IFN-γ,ROR-γt,T-bet in vitro,meanwhile it dramatically up-regulate the Th2/Treg cells response associated with increased levels of CD4+TGF-β+1cells and CD4+IL-10+cells in vivo and IL-4,IL-10,TGF-β1,Foxp3 and GATA3in vitro.CONCLUSION Considering the effective therapeutic effects of MAT on EAE,it′s worth to find its new values on other autoimmune diseases.展开更多
Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern...Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern concept of Tregs was catalyzed by Shimon Sakaguchi's identification of CD4+CD25+suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function;together with landmark FOXP3 genetic discoveries by Mary E.Brunkow and Fred Ramsdell,these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine.Under normal physiological conditions,FOXP3+Treg cells restrain autoreactive lymphocytes,prevent excessive inflammation,and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines,thereby protecting tissues from immune-mediated damage.Disruption of Treg abundance,stability,or suppressive capacity can therefore lead to immune dysregulation and disease.Over the past two decades,Treg cells have become a major focus of immunology because their roles are highly context-dependent.In autoimmune and chronic inflammatory diseases,impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury,supporting therapeutic approaches designed to enhance Treg cell number,stability,and suppressive potency.In contrast,many cancers exploit Treg cells by promoting their expansion,activation,and recruitment into the tumor microenvironment(TME),where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function,limiting dendritic cell activation,and fostering immune escape.In both settings,immune checkpoint pathways critically influence Treg cell biology.Beyond PD-1/PD-L1 and CTLA-4,emerging checkpoints and costimulatory receptors,including TIGIT,TIM-3,LAG-3,and OX40,modulate Treg cell generation,stability,and suppressive functions,thereby shaping the balance between tolerance and immunity.Meanwhile,immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors;lipid utilization and mitochondrial programs,among other metabolic axes,enable Treg cells to persist in nutrient-and oxygen-restricted microenvironments,while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner.In this review,we summarize the discovery and defining biological features of Treg cells,highlight core suppressive mechanisms and regulatory circuits,and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion.We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease,or selectively depleting,functionally inhibiting,and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy.Overall we discuss how deeper insight into Treg heterogeneity,checkpoint control,and immunometabolic regulation may enable more precise Treg celldirected interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.展开更多
AIM:Regulatory T cells(Tregs)are a specialized subset of CD4^(+)T cells primarily involved in im⁃munosuppressive functions.AMP-activated protein kinase(AMPK)serves as a metabolic sensor that governs the differen⁃tiati...AIM:Regulatory T cells(Tregs)are a specialized subset of CD4^(+)T cells primarily involved in im⁃munosuppressive functions.AMP-activated protein kinase(AMPK)serves as a metabolic sensor that governs the differen⁃tiation,maturation,and immune functions of Tregs through metabolic reprogramming.However,the impact of AMPKα1(the catalytic subunit of AMPK)knockout specifically in Tregs on the host's immune microenvironment remains largely un⁃explored.METHODS:Histological changes in immune organs were assessed using HE staining.The types of immune cells and their relative population percentages in immune organs and blood were quantified through flow cytometry in both AMPKα1flox/flox(AMPKα1^(fl/fl))mice and Treg-specific AMPKα1 knockout mice(AMPKα1^(fl/fl)Foxp3^(cre)mice).RESULTS:Compared to AMPKα1^(fl/fl)mice,the percentage of eosinophils in the bone marrow of AMPKα1^(fl/fl)Foxp3^(cre)mice was significant⁃ly reduced.Additionally,while the thymus of AMPKα1^(fl/fl)Foxp3^(cre)mice exhibited normal structure,both its size and the ratio of thymus weight to body weight were significantly decreased.The knockout of AMPKα1 in Tregs led to a notable reduction in the total percentage of immature double-negative(DN)cells.Consequently,the percentage of CD4^(+)T cells derived from these DN cells also decreased,even though the percentages of DN1 and DN4 cells were higher in the thymus of AMPKα1^(fl/fl)Foxp3^(cre)mice compared to AMPKα1^(fl/fl)mice.Importantly,the proportion of Siglec-F+CD11b^(+)eosinophils in the thymus was significantly lower in AMPKα1^(fl/fl)Foxp3^(cre)mice.Knockout of AMPKα1 in Tregs resulted in a marked increase in the percentage of CD4^(+)T cells in peripheral blood,alongside a decrease in the proportion of mature CD8^(+)T cells.Similarly,the proportion of CD4^(+)T cells in the spleen of AMPKα1^(fl/fl)Foxp3^(cre)mice was elevated compared to AMPKα1^(fl/fl)mice.In contrast,the proportion of neutrophils significantly decreased,while mononuclear cell proportions increased in the spleen of AMPKα1^(fl/fl)Foxp3^(cre)mice.In lymph nodes,the medullary boundaries in AMPKα1^(fl/fl)Foxp3^(cre)mice were blurred,and the lymphoid follicles were missing,a feature not observed in AMPKα1^(fl/fl)mice.Furthermore,the knockout of AMPKα1 in Tregs reduced the CD3^(+)T cell population,particularly the CD8^(+)T cell population,in lymph nodes.Although the mature Treg cell population was significantly lower in AMPKα1^(fl/fl)Foxp3^(cre)mice,the percentage of CD4^(+)T cells was markedly in⁃creased.In contrast,there was no statistically significant difference in granulocyte populations between AMPKα1^(fl/fl)Foxp3^(cre)and AMPKα1^(fl/fl)mice.CONCLUSION:The populations of mature Tregs,CD8^(+)T cells and eosinophils in various im⁃mune organs were significantly altered in mice with Treg-specific AMPKα1 knockout,suggesting a potential remodeling of the host immune microenvironment in response to inflammatory stimuli.展开更多
文摘Kang et al.published a research article on the treatment of ischemic stroke using engineered Treg cells(Kang et al.,Prog Biochem Biophys,2025,52(4):946-956.DOI:10.16476/j.pibb.2025.0019).Their study mainly explores the immunoregulatory role of regulatory T(Treg)cells in ischemic stroke,providing an innovative therapeutic strategy.Neuroinflammation is a major driver of secondary injury after stroke.Existing treatments focus on vascular recanalization while neglecting immune regulation.Their study proposes to modulate neuroinflammation through in vitro-induced Treg cells,offering a novel approach distinct from traditional thrombolysis and endovascular interventions.
基金The project supported by National Natural Science Foundation of China(31570357)
文摘OBJECTIVE Experimental autoimmune encephalomyelitis(EAE),the classical animal model for multiple sclerosis(MS)is triggered by an impaired balance of T helper(Th)cells and regulatory T(Tregs)cells.Matrine(MAT),a quinolizidine alkaloid derived from the herb Radix Sophorae Flave,has been shown to ameliorate the clinical signs,inflammatory infiltration,demyelination in acute EAE rats.However,whether MAT protect from EAE by adjusting Th and Treg cells response in specific-cellular and molecular level is unknown.METHODS Herein,MAT was tested for its effects on Th1,Th2,Th17 and Treg cells in the spinal cord of EAE mice and splenocyte-extracted from EAE mice with MOG35-55-restimulated,respectively.RESULTS Our findings revealed that MAT significantly inhibit the proliferation of splenocyte,and remarkably down-regulate the differentiation of Th1/Th17 cells with decreased expressions of CD4+IFN-γ+cells and CD4+IL-17+cells in vivo and IL-17,IFN-γ,ROR-γt,T-bet in vitro,meanwhile it dramatically up-regulate the Th2/Treg cells response associated with increased levels of CD4+TGF-β+1cells and CD4+IL-10+cells in vivo and IL-4,IL-10,TGF-β1,Foxp3 and GATA3in vitro.CONCLUSION Considering the effective therapeutic effects of MAT on EAE,it′s worth to find its new values on other autoimmune diseases.
文摘Regulatory T cells(Treg cells)are a specialized subset of CD4+T cells defined by expression of the lineage-specifying transcription factor FOXP3 and a potent capacity to maintain peripheral immune tolerance.The modern concept of Tregs was catalyzed by Shimon Sakaguchi's identification of CD4+CD25+suppressive T cells and subsequent work establishing FOXP3 as a central determinant of Treg cell development and function;together with landmark FOXP3 genetic discoveries by Mary E.Brunkow and Fred Ramsdell,these advances transformed understanding of immune homeostasis and were recognized by the 2025 Nobel Prize in Physiology or Medicine.Under normal physiological conditions,FOXP3+Treg cells restrain autoreactive lymphocytes,prevent excessive inflammation,and shape antigen-presenting cell activity through contact-dependent pathways and suppressive cytokines,thereby protecting tissues from immune-mediated damage.Disruption of Treg abundance,stability,or suppressive capacity can therefore lead to immune dysregulation and disease.Over the past two decades,Treg cells have become a major focus of immunology because their roles are highly context-dependent.In autoimmune and chronic inflammatory diseases,impaired Treg cell function or insufficient Treg activity contributes to loss of tolerance and persistent tissue injury,supporting therapeutic approaches designed to enhance Treg cell number,stability,and suppressive potency.In contrast,many cancers exploit Treg cells by promoting their expansion,activation,and recruitment into the tumor microenvironment(TME),where they blunt antitumor immunity by suppressing cytotoxic T-cell priming and effector function,limiting dendritic cell activation,and fostering immune escape.In both settings,immune checkpoint pathways critically influence Treg cell biology.Beyond PD-1/PD-L1 and CTLA-4,emerging checkpoints and costimulatory receptors,including TIGIT,TIM-3,LAG-3,and OX40,modulate Treg cell generation,stability,and suppressive functions,thereby shaping the balance between tolerance and immunity.Meanwhile,immunometabolic adaptations further tune Treg cell fitness and function in inflamed tissues and tumors;lipid utilization and mitochondrial programs,among other metabolic axes,enable Treg cells to persist in nutrient-and oxygen-restricted microenvironments,while microenvironmental stress can drive functional remodeling or fragility in a subset-dependent manner.In this review,we summarize the discovery and defining biological features of Treg cells,highlight core suppressive mechanisms and regulatory circuits,and synthesize evidence for the dual roles of Treg cells in preventing autoimmunity yet enabling tumor immune evasion.We further outline current and emerging therapeutic strategies aimed at augmenting Treg cell activity to restore tolerance in autoimmune disease,or selectively depleting,functionally inhibiting,and reprogramming tumor-resident Treg cells to enhance cancer immunotherapy.Overall we discuss how deeper insight into Treg heterogeneity,checkpoint control,and immunometabolic regulation may enable more precise Treg celldirected interventions and inform next-generation immunotherapeutic combinations across immune-mediated and malignant diseases.
基金Supported by the National Natural Science Foundation of China(No.81800423)the Guangdong Medical Science and Technology Research project(No.B2022102)。
文摘AIM:Regulatory T cells(Tregs)are a specialized subset of CD4^(+)T cells primarily involved in im⁃munosuppressive functions.AMP-activated protein kinase(AMPK)serves as a metabolic sensor that governs the differen⁃tiation,maturation,and immune functions of Tregs through metabolic reprogramming.However,the impact of AMPKα1(the catalytic subunit of AMPK)knockout specifically in Tregs on the host's immune microenvironment remains largely un⁃explored.METHODS:Histological changes in immune organs were assessed using HE staining.The types of immune cells and their relative population percentages in immune organs and blood were quantified through flow cytometry in both AMPKα1flox/flox(AMPKα1^(fl/fl))mice and Treg-specific AMPKα1 knockout mice(AMPKα1^(fl/fl)Foxp3^(cre)mice).RESULTS:Compared to AMPKα1^(fl/fl)mice,the percentage of eosinophils in the bone marrow of AMPKα1^(fl/fl)Foxp3^(cre)mice was significant⁃ly reduced.Additionally,while the thymus of AMPKα1^(fl/fl)Foxp3^(cre)mice exhibited normal structure,both its size and the ratio of thymus weight to body weight were significantly decreased.The knockout of AMPKα1 in Tregs led to a notable reduction in the total percentage of immature double-negative(DN)cells.Consequently,the percentage of CD4^(+)T cells derived from these DN cells also decreased,even though the percentages of DN1 and DN4 cells were higher in the thymus of AMPKα1^(fl/fl)Foxp3^(cre)mice compared to AMPKα1^(fl/fl)mice.Importantly,the proportion of Siglec-F+CD11b^(+)eosinophils in the thymus was significantly lower in AMPKα1^(fl/fl)Foxp3^(cre)mice.Knockout of AMPKα1 in Tregs resulted in a marked increase in the percentage of CD4^(+)T cells in peripheral blood,alongside a decrease in the proportion of mature CD8^(+)T cells.Similarly,the proportion of CD4^(+)T cells in the spleen of AMPKα1^(fl/fl)Foxp3^(cre)mice was elevated compared to AMPKα1^(fl/fl)mice.In contrast,the proportion of neutrophils significantly decreased,while mononuclear cell proportions increased in the spleen of AMPKα1^(fl/fl)Foxp3^(cre)mice.In lymph nodes,the medullary boundaries in AMPKα1^(fl/fl)Foxp3^(cre)mice were blurred,and the lymphoid follicles were missing,a feature not observed in AMPKα1^(fl/fl)mice.Furthermore,the knockout of AMPKα1 in Tregs reduced the CD3^(+)T cell population,particularly the CD8^(+)T cell population,in lymph nodes.Although the mature Treg cell population was significantly lower in AMPKα1^(fl/fl)Foxp3^(cre)mice,the percentage of CD4^(+)T cells was markedly in⁃creased.In contrast,there was no statistically significant difference in granulocyte populations between AMPKα1^(fl/fl)Foxp3^(cre)and AMPKα1^(fl/fl)mice.CONCLUSION:The populations of mature Tregs,CD8^(+)T cells and eosinophils in various im⁃mune organs were significantly altered in mice with Treg-specific AMPKα1 knockout,suggesting a potential remodeling of the host immune microenvironment in response to inflammatory stimuli.
