BACKGROUND The endoplasmic reticulum(ER)is closely related to a wide range of cellular functions and is a key component to maintain and restore metabolic health.Type 2 diabetes mellitus(T2DM)is a serious threat to hum...BACKGROUND The endoplasmic reticulum(ER)is closely related to a wide range of cellular functions and is a key component to maintain and restore metabolic health.Type 2 diabetes mellitus(T2DM)is a serious threat to human health,but the ER stress(ERS)-related mechanisms in T2DM have not been fully elucidated.AIM To identify potential ERS-related mechanisms and crucial biomarkers in T2DM.METHODS We conducted gene set enrichment analysis(GSEA)and gene set variation analysis(GSVA)in myoblast and myotube form GSE166502,and obtained the differentially expressed genes(DEGs).After intersecting with ERS-related genes,we obtained ERS-related DEGs.Finally,functional analyses,immune infiltration,and several networks were established.RESULTS Through GSEA and GSVA,we identified several metabolic and immune-related pathways.We obtained 227 ERS-related DEGs and constructed several important networks that help to understand the mechanisms and treatment of T2DM.Finally,memory CD4^(+)T cells accounted for the largest proportion of immune cells.CONCLUSION This study revealed ERS-related mechanisms in T2DM,which might contribute to new ideas and insights into the mechanisms and treatment of T2DM.展开更多
The peripheral repertoire of CD4+ T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4+ T cells can be activated in physiological conditions as in the c...The peripheral repertoire of CD4+ T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4+ T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4+ lymphocytes activated by dendritic cells (DCs) presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells (Tmem) from primary effectors activated with mature autologous DCs plus interleukin (IL)-2 (Tmauto), simulating the circumstances of an active immune response, or allogeneic DCs (Tmallo). Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors (demonstrated by CD25 downregulation) particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tmauto and TmaHo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tma^o were closely related to conventional memory lymphocytes based on Erk-l/2 activation, whereas Tmauto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD4+ T lymphocytes recognizing self-peptides in the setting of strong costimulation.展开更多
The abnormal activation of CD4^(+)CD45RO+memory T(Tm)cells plays an important role in the pathogenesis of rheumatoid arthritis(RA).Previous studies have shown that CD147 participates in T-cell activation.However,it re...The abnormal activation of CD4^(+)CD45RO+memory T(Tm)cells plays an important role in the pathogenesis of rheumatoid arthritis(RA).Previous studies have shown that CD147 participates in T-cell activation.However,it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients.In this study,we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients.The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activation and proliferation and further restrained osteoclastogenesis.Using a structural–functional approach,we depicted the interface between 5A12 and CD147.This allowed us to identify two critical residues,Lys63 and Asp65,as potential targets for RA treatment,as the double mutation K63A/D65A inhibited Tm-cell activation,mimicking the neutralization by 5A12.This study provides not only a theoretical basis for a“CD147-Tm/Osteoclast-RA chain”for the potential prevention and treatment of RA or other T-cell-mediated autoimmune diseases but also a new target for related drug design and development.展开更多
The ultimate goal of antitumor vaccines is to develop memory CD8+ cytotoxic T lymphocytes (CTLs), which are critical mediators of antitumor immunity. We previously demonstrated that the ovalbumin (OVA)-specific ...The ultimate goal of antitumor vaccines is to develop memory CD8+ cytotoxic T lymphocytes (CTLs), which are critical mediators of antitumor immunity. We previously demonstrated that the ovalbumin (OVA)-specific CD4+ T cell-based (OVA-TExo) vaccine generated using OVA-pulsed dendritic cell (DCovA)-released exosomes (EXOovA) stimulate CTL responses via IL-2 and costimulatory CD80 signaling. To assess the potential involvement of other costimulatory pathways and to define the key constituent of costimulation for memory CTL development, we first immunized wild-type (WT) C57BIJ6 and gene-knockout mice with WT CD4~ OVA-TExo cells or OVA-TExo cells with various molecular deficiencies. We then assessed OVA-specific primary and recall CTL responses using PE-H-2Kb/ 0VA257_264 tetramer and FITC-anti-CD8 antibody staining by flow cytometry. We also examined antitumor immunity against the OVA-expressing B16 melanoma cell line BL6-1OovA. We demonstrated that CD4+ OVA-TExo cells stimulated more efficient CTL responses compared to DCovA. By assessing primary and recall CTL responses in mice immunized with OVA-TExo or with OVA-TExo lacking the costimulatory molecules CD4OL, 4-1BBL or OX4OL, we demonstrated that these costimulatory signals are dispensable for CTL priming by OVA-TExo. Interestingly, CD4OL, but not 4-1BBL or OX4OL, plays a crucial role in the development of functional memory CTLs against BL6-1OovA tumors. Overall, this work suggests that a novel CD4+ T cell-based vaccine that is capable of stimulating long-term functional CTL memory via CD40L signaling may represent a novel, efficient approach to antitumor vaccination.展开更多
Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obe...Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obese status.In a weight gain-loss-regain model,we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain.This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice.Surprisingly,such obesity memory was abrogated by dexamethasone treatment,whereas immunodeficient Rag1−/−and H2A−/−mice failed to establish such memory.Rag1−/−mice repossessed the obesity memory when immune cells or CD4+T cells isolated from previously obese mice were transferred.Furthermore,depletion of CD4+T cells led to obesity memory ablation.Taken together,we conclude that CD4+T cells mediate obesity memory and promote weight regain.展开更多
文摘BACKGROUND The endoplasmic reticulum(ER)is closely related to a wide range of cellular functions and is a key component to maintain and restore metabolic health.Type 2 diabetes mellitus(T2DM)is a serious threat to human health,but the ER stress(ERS)-related mechanisms in T2DM have not been fully elucidated.AIM To identify potential ERS-related mechanisms and crucial biomarkers in T2DM.METHODS We conducted gene set enrichment analysis(GSEA)and gene set variation analysis(GSVA)in myoblast and myotube form GSE166502,and obtained the differentially expressed genes(DEGs).After intersecting with ERS-related genes,we obtained ERS-related DEGs.Finally,functional analyses,immune infiltration,and several networks were established.RESULTS Through GSEA and GSVA,we identified several metabolic and immune-related pathways.We obtained 227 ERS-related DEGs and constructed several important networks that help to understand the mechanisms and treatment of T2DM.Finally,memory CD4^(+)T cells accounted for the largest proportion of immune cells.CONCLUSION This study revealed ERS-related mechanisms in T2DM,which might contribute to new ideas and insights into the mechanisms and treatment of T2DM.
文摘The peripheral repertoire of CD4+ T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4+ T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4+ lymphocytes activated by dendritic cells (DCs) presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells (Tmem) from primary effectors activated with mature autologous DCs plus interleukin (IL)-2 (Tmauto), simulating the circumstances of an active immune response, or allogeneic DCs (Tmallo). Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors (demonstrated by CD25 downregulation) particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tmauto and TmaHo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tma^o were closely related to conventional memory lymphocytes based on Erk-l/2 activation, whereas Tmauto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD4+ T lymphocytes recognizing self-peptides in the setting of strong costimulation.
基金supported by grant(2015CB553704)from the National Basic Research Program of China,grants(2013ZX09301301 and 2014ZX09508002-002)+3 种基金from the National Science and Technology Major Project of China,grant(2017YFC0909002)from the National Key Research Project of China,grant(31470792)from the National Natural Science Foundation of China and grant(XDB08030102)from the Strategic Priority Research Program of the Chinese Academy of Sciences.
文摘The abnormal activation of CD4^(+)CD45RO+memory T(Tm)cells plays an important role in the pathogenesis of rheumatoid arthritis(RA).Previous studies have shown that CD147 participates in T-cell activation.However,it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients.In this study,we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients.The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activation and proliferation and further restrained osteoclastogenesis.Using a structural–functional approach,we depicted the interface between 5A12 and CD147.This allowed us to identify two critical residues,Lys63 and Asp65,as potential targets for RA treatment,as the double mutation K63A/D65A inhibited Tm-cell activation,mimicking the neutralization by 5A12.This study provides not only a theoretical basis for a“CD147-Tm/Osteoclast-RA chain”for the potential prevention and treatment of RA or other T-cell-mediated autoimmune diseases but also a new target for related drug design and development.
文摘The ultimate goal of antitumor vaccines is to develop memory CD8+ cytotoxic T lymphocytes (CTLs), which are critical mediators of antitumor immunity. We previously demonstrated that the ovalbumin (OVA)-specific CD4+ T cell-based (OVA-TExo) vaccine generated using OVA-pulsed dendritic cell (DCovA)-released exosomes (EXOovA) stimulate CTL responses via IL-2 and costimulatory CD80 signaling. To assess the potential involvement of other costimulatory pathways and to define the key constituent of costimulation for memory CTL development, we first immunized wild-type (WT) C57BIJ6 and gene-knockout mice with WT CD4~ OVA-TExo cells or OVA-TExo cells with various molecular deficiencies. We then assessed OVA-specific primary and recall CTL responses using PE-H-2Kb/ 0VA257_264 tetramer and FITC-anti-CD8 antibody staining by flow cytometry. We also examined antitumor immunity against the OVA-expressing B16 melanoma cell line BL6-1OovA. We demonstrated that CD4+ OVA-TExo cells stimulated more efficient CTL responses compared to DCovA. By assessing primary and recall CTL responses in mice immunized with OVA-TExo or with OVA-TExo lacking the costimulatory molecules CD4OL, 4-1BBL or OX4OL, we demonstrated that these costimulatory signals are dispensable for CTL priming by OVA-TExo. Interestingly, CD4OL, but not 4-1BBL or OX4OL, plays a crucial role in the development of functional memory CTLs against BL6-1OovA tumors. Overall, this work suggests that a novel CD4+ T cell-based vaccine that is capable of stimulating long-term functional CTL memory via CD40L signaling may represent a novel, efficient approach to antitumor vaccination.
基金This work was supported by the National Natural Science Foundation of China(Grant 31301217)the Ministry of Science and Technology of China(Grants 2015BAI08B02 and 2014BAI02B01).
文摘Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obese status.In a weight gain-loss-regain model,we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain.This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice.Surprisingly,such obesity memory was abrogated by dexamethasone treatment,whereas immunodeficient Rag1−/−and H2A−/−mice failed to establish such memory.Rag1−/−mice repossessed the obesity memory when immune cells or CD4+T cells isolated from previously obese mice were transferred.Furthermore,depletion of CD4+T cells led to obesity memory ablation.Taken together,we conclude that CD4+T cells mediate obesity memory and promote weight regain.