Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells....Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells.They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues.Here,wedemonstrate thatmyeloid cell-specific genetic deletion of PTP1B(LysM PTP1B)leads to defects in lipopolysaccharide-driven bone marrow-derivedDC(BMDC)activation associated with increased levels of phosphorylated Stat3.We showthatmyeloid cell-specific PTP1Bdeletion also causes decreased migratory capacity of epidermal DC,aswell as reduced CCR7 expression and chemotaxis to CCL19 by BMDC.PTP1B deficiency in BMDC also impairs their migration in vivo.Further,immature LysM PTP1B BMDC display fewer podosomes,increased levels of phosphorylated Src at tyrosine 527,and loss of Src localization to podosome puncta.In co-culture with T cells,LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC.Finally,LysMPTP1BBMDCfail to present antigen to T cells as efficiently as controlBMDC.These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.展开更多
Aim:Patients with glioblastomas demonstrate well‑documented immunological impairments including decreased numbers of mature dendritic cells(DCs).Recent data identified karyopherin a2(KPNA2),a nucleocytoplasmic shuttli...Aim:Patients with glioblastomas demonstrate well‑documented immunological impairments including decreased numbers of mature dendritic cells(DCs).Recent data identified karyopherin a2(KPNA2),a nucleocytoplasmic shuttling receptor,as diagnostic and prognostic biomarker for gliomas.The aim of this ongoing study is to correlate parameters of immunity and nucleocytoplasmic transport in glioblastoma patients.Methods:We preoperatively collected serum from 17 patients with glioblastomas and determined DC subsets(HLA DR+Lin-,CD34-,CD45+,CD123+,CD11+were analyzed)using a 6‑color flow cytometry panel.Expression levels of KPNA2 and nuclear accumulation of p53 were evaluated semi‑quantitatively by immunohistochemistry.O6‑methylguanine DNA methyltransferase(MGMT)and isocitrate dehydrogenase‑1(IDH‑1)status were assessed by pyrosequencing and immunohistochemistry,respectively.Results:Median expression levels for both KPNA2 and p53 were 5-10%.IDH‑1‑R132H mutation and MGMT promoter hypermethylation was detected in 3/16 and 1/9 patients,respectively.Mean counts of total mature DCs,myeloid DCs and plasmacytoid DCs were 9.6,2.1,3.4 cells/μL.A preliminary analysis suggests an association between low KPNA2 nuclear expression and increased numbers of mature DCs.However,this correlation did not reach statistical significance so far(P=0.077).Conclusion:Our preliminary data may indicate a role of KPNA2 in the impaired maturation of DCs observed in glioblastoma patients.展开更多
基金supported by Saving Sight in Grampian and the Development Trust of the University of Aberdeen。
文摘Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells.They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues.Here,wedemonstrate thatmyeloid cell-specific genetic deletion of PTP1B(LysM PTP1B)leads to defects in lipopolysaccharide-driven bone marrow-derivedDC(BMDC)activation associated with increased levels of phosphorylated Stat3.We showthatmyeloid cell-specific PTP1Bdeletion also causes decreased migratory capacity of epidermal DC,aswell as reduced CCR7 expression and chemotaxis to CCL19 by BMDC.PTP1B deficiency in BMDC also impairs their migration in vivo.Further,immature LysM PTP1B BMDC display fewer podosomes,increased levels of phosphorylated Src at tyrosine 527,and loss of Src localization to podosome puncta.In co-culture with T cells,LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC.Finally,LysMPTP1BBMDCfail to present antigen to T cells as efficiently as controlBMDC.These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.
文摘Aim:Patients with glioblastomas demonstrate well‑documented immunological impairments including decreased numbers of mature dendritic cells(DCs).Recent data identified karyopherin a2(KPNA2),a nucleocytoplasmic shuttling receptor,as diagnostic and prognostic biomarker for gliomas.The aim of this ongoing study is to correlate parameters of immunity and nucleocytoplasmic transport in glioblastoma patients.Methods:We preoperatively collected serum from 17 patients with glioblastomas and determined DC subsets(HLA DR+Lin-,CD34-,CD45+,CD123+,CD11+were analyzed)using a 6‑color flow cytometry panel.Expression levels of KPNA2 and nuclear accumulation of p53 were evaluated semi‑quantitatively by immunohistochemistry.O6‑methylguanine DNA methyltransferase(MGMT)and isocitrate dehydrogenase‑1(IDH‑1)status were assessed by pyrosequencing and immunohistochemistry,respectively.Results:Median expression levels for both KPNA2 and p53 were 5-10%.IDH‑1‑R132H mutation and MGMT promoter hypermethylation was detected in 3/16 and 1/9 patients,respectively.Mean counts of total mature DCs,myeloid DCs and plasmacytoid DCs were 9.6,2.1,3.4 cells/μL.A preliminary analysis suggests an association between low KPNA2 nuclear expression and increased numbers of mature DCs.However,this correlation did not reach statistical significance so far(P=0.077).Conclusion:Our preliminary data may indicate a role of KPNA2 in the impaired maturation of DCs observed in glioblastoma patients.
