As an important component of innate immunity,human circulatingγδT cells function in rapid responses to infections and tumorigenesis.MicroRNAs(miRNAs)play a critical regulatory role in multiple biological processes a...As an important component of innate immunity,human circulatingγδT cells function in rapid responses to infections and tumorigenesis.MicroRNAs(miRNAs)play a critical regulatory role in multiple biological processes and diseases.Therefore,how the functions of circulating humanγδT cells are regulated by miRNAs merits investigation.In this study,we profiled the miRNA expression patterns in human peripheralγδT cells from 21 healthy donors and identified 14 miRNAs that were differentially expressed between peripheralαβT cells andγδT cells.Of the 14 identified genes,7 miRNAs were downregulated,including miR-150-5p,miR-450a-5p,miR-193b-3p,miR-365a-3p,miR-31-5p,miR-125b-5p and miR-99a-5p,whereas the other 7 miRNAs were upregulated,including miR-34a-5p,miR-16-5p,miR-15b-5p,miR-24-3p,miR-22-3p,miR-22-5p and miR-9-5p,inγδT cells compared withαβT cells.In subsequent functional studies,we found that both miR-125b-5p and miR-99a-5p downregulatedγδT cell activation and cytotoxicity to tumor cells.Overexpression of miR-125b-5p or miR-99a-5p inγδT cells inhibitedγδT cell activation and promotedγδT cell apoptosis.Additionally,miR-125b-5p knockdown facilitated the cytotoxicity ofγδT cells toward tumor cells in vitro by increasing degranulation and secretion of IFN-γand TNF-α.Our findings improve the understanding of the regulatory functions of miRNAs inγδT cell activation and cytotoxicity,which has implications for interventional approaches toγδT cell-mediated cancer therapy.展开更多
B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing...B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing to LNs has remained unclear.We show here that nuclear factor(NF)-κB-inducing kinase(NIK),a kinase mediating activation of the noncanonical NF-κB pathway,functions in lymphatic endothelial cells(LECs)to regulate B-cell homing to LNs.LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs.The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen.B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells.We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs.Although CCL19 is also expressed in blood endothelial cells(BECs),CXCL13 is not produced in BECs.These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.展开更多
基金by the National Natural Science Foundation of China(31500725,81673010,91542117,81471574 and 31471016)CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses(2016ZX310180-5 and 2017PT31004)+3 种基金the CAMS Initiative for Innovative Medicine(2016-I2M-1-008)the National Key Research and Development Program of China(2016YFA0101001 and 2016YFC0903900)Peking Union Medical College Foundation(No.3332015111)Peking Union Medical College Science Foundation for Young Scientists(No.3332015109).
文摘As an important component of innate immunity,human circulatingγδT cells function in rapid responses to infections and tumorigenesis.MicroRNAs(miRNAs)play a critical regulatory role in multiple biological processes and diseases.Therefore,how the functions of circulating humanγδT cells are regulated by miRNAs merits investigation.In this study,we profiled the miRNA expression patterns in human peripheralγδT cells from 21 healthy donors and identified 14 miRNAs that were differentially expressed between peripheralαβT cells andγδT cells.Of the 14 identified genes,7 miRNAs were downregulated,including miR-150-5p,miR-450a-5p,miR-193b-3p,miR-365a-3p,miR-31-5p,miR-125b-5p and miR-99a-5p,whereas the other 7 miRNAs were upregulated,including miR-34a-5p,miR-16-5p,miR-15b-5p,miR-24-3p,miR-22-3p,miR-22-5p and miR-9-5p,inγδT cells compared withαβT cells.In subsequent functional studies,we found that both miR-125b-5p and miR-99a-5p downregulatedγδT cell activation and cytotoxicity to tumor cells.Overexpression of miR-125b-5p or miR-99a-5p inγδT cells inhibitedγδT cell activation and promotedγδT cell apoptosis.Additionally,miR-125b-5p knockdown facilitated the cytotoxicity ofγδT cells toward tumor cells in vitro by increasing degranulation and secretion of IFN-γand TNF-α.Our findings improve the understanding of the regulatory functions of miRNAs inγδT cell activation and cytotoxicity,which has implications for interventional approaches toγδT cell-mediated cancer therapy.
基金by grants from the National Institutes of Health(GM84459,AI057555,AI104519 and AI64639)This study also used the NIH/NCI-supported resources under award number P30CA016672 at The MD Anderson Cancer CenterSZ was supported by a scholarship from the China Scholarship Council(CSC)under the Grant CSC 201506210393.
文摘B cells home to the lymph nodes(LNs)via high endothelial venules(HEVs)under the guidance of chemokines,particularly CXCL13.However,as CXCL13 is not directly made in HEVs,the molecular mechanism mediating B-cell homing to LNs has remained unclear.We show here that nuclear factor(NF)-κB-inducing kinase(NIK),a kinase mediating activation of the noncanonical NF-κB pathway,functions in lymphatic endothelial cells(LECs)to regulate B-cell homing to LNs.LEC-conditional deletion of NIK in mice did not affect the integrity or global function of lymphatic vessels but caused a severe reduction in the frequency of B cells in LNs.The LEC-specific NIK deficiency did not affect the survival of B cells or the frequency of B cells in the spleen.B-cell adoptive transfer studies revealed that the LEC-specific NIK deletion impairs the ability of LNs to recruit B cells.We further show that NIK mediates expression of the chemokines CXCL13 and CCL19 in LECs.Although CCL19 is also expressed in blood endothelial cells(BECs),CXCL13 is not produced in BECs.These results suggest that NIK regulates naive B-cell homing to LNs via mediating production of the B-cell homing chemokine CXCL13 in LECs.