In a recent study published in Nature,Chen et al.1 investigated the potential of RBPJ knock-out to improve stability and function of induced regulatory T cells(iTreg cells).This finding could further enhance the utili...In a recent study published in Nature,Chen et al.1 investigated the potential of RBPJ knock-out to improve stability and function of induced regulatory T cells(iTreg cells).This finding could further enhance the utilization of these cells for adoptive immunotherapy in immune-related diseases.展开更多
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^(+)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
基金funded by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)Projektnummer 318346496(SFB1292/2)and 490846870(TRR355/1).
文摘In a recent study published in Nature,Chen et al.1 investigated the potential of RBPJ knock-out to improve stability and function of induced regulatory T cells(iTreg cells).This finding could further enhance the utilization of these cells for adoptive immunotherapy in immune-related diseases.
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.
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.
