Trogocytosis is a process which involves the transfer of membrane fragments and cell surface proteins between cells. Various types of T cells have been shown to be able to acquire membrane-bound proteins from antigen-...Trogocytosis is a process which involves the transfer of membrane fragments and cell surface proteins between cells. Various types of T cells have been shown to be able to acquire membrane-bound proteins from antigen-presenting cells and their functions can be modulated following trogocytosis. However, it is not known whether induced regulatory T cells （iTregs） can undergo trogocytosis, and if so, what the functional consequences of this process might entail. In this study, we show that iTregs can be generated from CD80-/-CD86-/- double knockout （DKO） mice. Using flow cytometry and confocal fluorescence microscopy, we demonstrate that iTregs generated from DKO mice are able to acquire both CD80 and CD86 from mature dendritic cells （mDCs） and that the acquisition of CD86 occurs to a higher extent than that of CD80. Furthermore, we found that after co-incubation with iTregs, dendritic cells （DCs） downregulate their surface expression of CD80 and CD86. The trogocytosis of both CD80 and CD86 occurs in a cytotoxic T lymphocyte-associated antigen-4 （CTLA-4）, CD28 and programmed death ligand-1 （PDL1）-independent manner. Importantly, we showed that iTregs that acquired CD86 from mDCs expressed higher activation markers and their ability to suppress naive CD4＋ T-cell proliferation was enhanced, compared to iTregs that did not acquire CD86. These data demonstrate, for the first time, that iTregs can acquire CD80 and CD86 from mDCs, and the acquisition of CD86 may enhance their suppressive function. These findings provide novel understanding of the interaction between iTregs and DCs, suggesting that trogocytosis may play a significant role in iTreg-mediated immune suppression.展开更多
CD4+CD25+FOXP3+的调节T细胞(regulatory T cells,Treg)在维持机体免疫平衡方面起着重要的作用。体外扩增Treg细胞用于治疗自身免疫病、哮喘及诱导器官移植免疫耐受引起人们极大的兴趣。Treg细胞可分为2个亚群,分别为nTreg和iTreg,两者...CD4+CD25+FOXP3+的调节T细胞(regulatory T cells,Treg)在维持机体免疫平衡方面起着重要的作用。体外扩增Treg细胞用于治疗自身免疫病、哮喘及诱导器官移植免疫耐受引起人们极大的兴趣。Treg细胞可分为2个亚群,分别为nTreg和iTreg,两者有不同的生物学特性。nTreg在特定条件下,可以分泌具有促进炎症的IL-17;iTreg在体内可丢失FOXP3,失去其免疫抑制功能。Treg细胞用于临床治疗,还有许多问题需要研究解决。展开更多
CD4^(+)FOXP3^(+)Treg cells are central to the maintenance of self-tolerance and can be defective in autoimmunity.In autoimmune rheumatic diseases,dysfunctional self-tolerance,is to a large extent,caused by insufficien...CD4^(+)FOXP3^(+)Treg cells are central to the maintenance of self-tolerance and can be defective in autoimmunity.In autoimmune rheumatic diseases,dysfunctional self-tolerance,is to a large extent,caused by insufficient Treg-cell activity.Although nTregs have therapeutic effects in vivo,their relative scarcity and slow rate of in vitro expansion hinder the application of nTreg therapy.It was previously reported that EVs contribute significantly to the suppressive function of FOXP3^(+)Treg cells.Considering that the stability and plasticity of nTregs remain major challenges in vivo,we established EVs derived from in vitro TGF-β-induced Treg cells(iTreg-EVs)and assessed their functions in a murine model of autoimmune arthritis.The results demonstrated that iTreg-EVs preferentially homed to the pathological joint and efficiently prevented the imbalance in Th17/Treg cells in arthritic mice.Furthermore,we found that miR-449a-5p mediated Notch1 expression modulation and that miR-449a-5p knockdown abolished the effects of iTreg-EVs on effector T cells and regulatory T cells in vitro and in vivo.Taken together,our results show that iTreg-EVs control the inflammatory responses of recipient T cells through miR-449a-5p-dependent modulation of Notch1 and ameliorate the development and severity of arthritis,which may provide a potential cell-free strategy based on manipulating iTreg-EVs to prevent autoimmune arthritis.展开更多
文摘Trogocytosis is a process which involves the transfer of membrane fragments and cell surface proteins between cells. Various types of T cells have been shown to be able to acquire membrane-bound proteins from antigen-presenting cells and their functions can be modulated following trogocytosis. However, it is not known whether induced regulatory T cells （iTregs） can undergo trogocytosis, and if so, what the functional consequences of this process might entail. In this study, we show that iTregs can be generated from CD80-/-CD86-/- double knockout （DKO） mice. Using flow cytometry and confocal fluorescence microscopy, we demonstrate that iTregs generated from DKO mice are able to acquire both CD80 and CD86 from mature dendritic cells （mDCs） and that the acquisition of CD86 occurs to a higher extent than that of CD80. Furthermore, we found that after co-incubation with iTregs, dendritic cells （DCs） downregulate their surface expression of CD80 and CD86. The trogocytosis of both CD80 and CD86 occurs in a cytotoxic T lymphocyte-associated antigen-4 （CTLA-4）, CD28 and programmed death ligand-1 （PDL1）-independent manner. Importantly, we showed that iTregs that acquired CD86 from mDCs expressed higher activation markers and their ability to suppress naive CD4＋ T-cell proliferation was enhanced, compared to iTregs that did not acquire CD86. These data demonstrate, for the first time, that iTregs can acquire CD80 and CD86 from mDCs, and the acquisition of CD86 may enhance their suppressive function. These findings provide novel understanding of the interaction between iTregs and DCs, suggesting that trogocytosis may play a significant role in iTreg-mediated immune suppression.
文摘CD4+CD25+FOXP3+的调节T细胞(regulatory T cells,Treg)在维持机体免疫平衡方面起着重要的作用。体外扩增Treg细胞用于治疗自身免疫病、哮喘及诱导器官移植免疫耐受引起人们极大的兴趣。Treg细胞可分为2个亚群,分别为nTreg和iTreg,两者有不同的生物学特性。nTreg在特定条件下,可以分泌具有促进炎症的IL-17;iTreg在体内可丢失FOXP3,失去其免疫抑制功能。Treg细胞用于临床治疗,还有许多问题需要研究解决。
基金This study was supported by the National Key R&D Program of China(2017YFA0105801)the General Program of the National Natural Science Foundation of China(81871224).
文摘CD4^(+)FOXP3^(+)Treg cells are central to the maintenance of self-tolerance and can be defective in autoimmunity.In autoimmune rheumatic diseases,dysfunctional self-tolerance,is to a large extent,caused by insufficient Treg-cell activity.Although nTregs have therapeutic effects in vivo,their relative scarcity and slow rate of in vitro expansion hinder the application of nTreg therapy.It was previously reported that EVs contribute significantly to the suppressive function of FOXP3^(+)Treg cells.Considering that the stability and plasticity of nTregs remain major challenges in vivo,we established EVs derived from in vitro TGF-β-induced Treg cells(iTreg-EVs)and assessed their functions in a murine model of autoimmune arthritis.The results demonstrated that iTreg-EVs preferentially homed to the pathological joint and efficiently prevented the imbalance in Th17/Treg cells in arthritic mice.Furthermore,we found that miR-449a-5p mediated Notch1 expression modulation and that miR-449a-5p knockdown abolished the effects of iTreg-EVs on effector T cells and regulatory T cells in vitro and in vivo.Taken together,our results show that iTreg-EVs control the inflammatory responses of recipient T cells through miR-449a-5p-dependent modulation of Notch1 and ameliorate the development and severity of arthritis,which may provide a potential cell-free strategy based on manipulating iTreg-EVs to prevent autoimmune arthritis.
