目的探讨HIV-1慢性感染者CD8^+干细胞样记忆性T细胞(stem memory T cell,Tscm)免疫活化水平的变化特点及其活化对CD8^+T细胞功能耗竭的影响。方法选取24例未经治疗的HIV-1慢性期感染者和41名健康对照者,采用流式细胞术分别检测健康对照...目的探讨HIV-1慢性感染者CD8^+干细胞样记忆性T细胞(stem memory T cell,Tscm)免疫活化水平的变化特点及其活化对CD8^+T细胞功能耗竭的影响。方法选取24例未经治疗的HIV-1慢性期感染者和41名健康对照者,采用流式细胞术分别检测健康对照者和HIV-1感染者CD8^+Tscm的比例、CD8^+Tscm的免疫活化水平、CD8^+T细胞表面抑制性分子(CD160、PD-1、TIGIT、TIM-3和LAG-3)表达水平及CD8^+T细胞功能(分泌细胞因子IL-2、IFN-γ和TNF-α的能力);分析CD8^+Tscm的免疫活化水平与CD8^+T细胞抑制性分子表达及CD8^+T细胞功能的相关性。结果与健康对照者相比,HIV-1慢性期感染者CD8^+Tscm的比例显著下降,CD8^+Tscm免疫活化水平(CD38^+HLA-DR^+CD8^+Tscm比例)显著升高。HIV-1慢性期感染者CD8^+Tscm免疫活化水平与CD8^+T细胞分泌IL-2和TNF-α水平呈负相关。HIV-1慢性感染引起CD8^+T细胞抑制性分子(CD160、PD-1、TIGIT和LAG-3)上调,但活化的CD8^+Tscm仅与CD8^+T细胞抑制性分子TIGIT表达水平呈正相关。CD8^+T细胞抑制性分子TIGIT表达水平与CD8^+T细胞分泌IL-2和TNF-α水平呈负相关。结论 HIV-1慢性感染引起CD8^+Tscm的异常免疫活化,活化的CD8^+Tscm通过上调CD8^+T细胞抑制性分子TIGIT抑制CD8^+T细胞功能。展开更多
Donor selection determines the occurrence of acute graft-versus-host-disease(aGVHD)following allogeneic hematopoietic stem cell transplantation(allo-HSCT).To optimize the current clinical donor selection criteria and ...Donor selection determines the occurrence of acute graft-versus-host-disease(aGVHD)following allogeneic hematopoietic stem cell transplantation(allo-HSCT).To optimize the current clinical donor selection criteria and identify putative donor lymphocyte subsets associated with better recipient outcomes,we analyzed the peripheral CD4^(+)and CD8^(+)subsets in 80 granulocyte colonystimulating factor(G-CSF)mobilized donors and examined the aGVHD incidence of the corresponding 80 haploidentical and identical allo-HSCT recipients.The G-CSF-induced expansion of subsets varied among donors.We discovered a novel PD-1^(+)CD8^(+)CD45RA^(+)CCR7^(+)T lymphocyte subset in suitable donors that was significantly correlated with lower incidence of aGVHD and post-transplant anti-infection.The anti-aGVHD activity of this subset was confirmed in a validation cohort(n=30).Single-cell RNA sequencing revealed that this T cell subset exhibited transcriptomic features of stem cell-like memory T cell(TSCM)with both Treg and Teff activities which indicated its dual functions in aGVHD inhibition and graft-versus-leukemia(GVL)effect.Intriguingly,upon G-CSF mobilization,the donor PD-1^(+)CD8^(+)TSCM-like regulatory cells increased the PD-1 expression in a BCL6-dependent manner.Next,we showed that the mouse counterpart of this subset(PD-1^(+)CD8^(+)CD44^(-)CD62L^(+))ameliorated aGVHD,and confirmed the existence of this subset in clinical recipients.In summary,we,for the first time,identified a novel donor peripheral T cell subset suppressing aGVHD while promoting the immune reconstitution of recipients.It may serve as an indicator for optimal haploidentical and identical donor selection.Importantly,the dual Treg and Teff function of these T cells makes it a promising treatment for not only aGVHD but also auto-immune diseases.展开更多
目的探究环黄芪醇(cycloastragenol,CAG)联合细胞因子IL-7和IL-15对人脐带血T细胞体外扩增和CD8^+T细胞亚群中干细胞样中心记忆性T细胞(stem cell-like central memory T cells,TSCM)比例的影响,为基于T细胞的肿瘤细胞免疫治疗研究奠定...目的探究环黄芪醇(cycloastragenol,CAG)联合细胞因子IL-7和IL-15对人脐带血T细胞体外扩增和CD8^+T细胞亚群中干细胞样中心记忆性T细胞(stem cell-like central memory T cells,TSCM)比例的影响,为基于T细胞的肿瘤细胞免疫治疗研究奠定实验基础。方法采集健康产妇脐带血,通过密度梯度离心法分离获得脐带血单个核细胞(umbilical cord blood mononuclear cells,UCBMC),利用CD3/CD28抗体偶联磁珠刺激活化后,采用不同浓度的CAG(0、0.04、0.2、1、5μmol/L)联合IL-7和IL-15连续培养,利用多色流式细胞术分别测定T细胞的增殖程度以及CD8^+T细胞中TSCM比例的变化情况。结果 0.2μmol/L CAG与IL-7和IL-15细胞因子联用组促T细胞扩增作用显著高于其他浓度CAG与细胞因子IL-7和IL-15联用组或单独使用细胞因子IL-7和IL-15组。同时,0.2μmol/L CAG联用IL-7和IL-15组还可以促进CD8^+T中CD197^+CD45RA+细胞表型的表达,即维持CD8^+T中高比例的TSCM亚群。结论 0.2μmol/L CAG联合IL-7和IL-15可以显著提高活化T细胞扩增能力,并能保持CD8^+T细胞中高比例的TSCM亚群。展开更多
文摘目的探讨HIV-1慢性感染者CD8^+干细胞样记忆性T细胞(stem memory T cell,Tscm)免疫活化水平的变化特点及其活化对CD8^+T细胞功能耗竭的影响。方法选取24例未经治疗的HIV-1慢性期感染者和41名健康对照者,采用流式细胞术分别检测健康对照者和HIV-1感染者CD8^+Tscm的比例、CD8^+Tscm的免疫活化水平、CD8^+T细胞表面抑制性分子(CD160、PD-1、TIGIT、TIM-3和LAG-3)表达水平及CD8^+T细胞功能(分泌细胞因子IL-2、IFN-γ和TNF-α的能力);分析CD8^+Tscm的免疫活化水平与CD8^+T细胞抑制性分子表达及CD8^+T细胞功能的相关性。结果与健康对照者相比,HIV-1慢性期感染者CD8^+Tscm的比例显著下降,CD8^+Tscm免疫活化水平(CD38^+HLA-DR^+CD8^+Tscm比例)显著升高。HIV-1慢性期感染者CD8^+Tscm免疫活化水平与CD8^+T细胞分泌IL-2和TNF-α水平呈负相关。HIV-1慢性感染引起CD8^+T细胞抑制性分子(CD160、PD-1、TIGIT和LAG-3)上调,但活化的CD8^+Tscm仅与CD8^+T细胞抑制性分子TIGIT表达水平呈正相关。CD8^+T细胞抑制性分子TIGIT表达水平与CD8^+T细胞分泌IL-2和TNF-α水平呈负相关。结论 HIV-1慢性感染引起CD8^+Tscm的异常免疫活化,活化的CD8^+Tscm通过上调CD8^+T细胞抑制性分子TIGIT抑制CD8^+T细胞功能。
基金supported by grants from the National Key Research and Development Program of China(2017YFA0104500)the Program for Scientific and Technological Innovation from the Science and Technology Commission of Shanghai Municipality(22490760400)+1 种基金the National Natural Science Foundation of China(Grant No.82071856,81671579,81930004)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(2060302).
文摘Donor selection determines the occurrence of acute graft-versus-host-disease(aGVHD)following allogeneic hematopoietic stem cell transplantation(allo-HSCT).To optimize the current clinical donor selection criteria and identify putative donor lymphocyte subsets associated with better recipient outcomes,we analyzed the peripheral CD4^(+)and CD8^(+)subsets in 80 granulocyte colonystimulating factor(G-CSF)mobilized donors and examined the aGVHD incidence of the corresponding 80 haploidentical and identical allo-HSCT recipients.The G-CSF-induced expansion of subsets varied among donors.We discovered a novel PD-1^(+)CD8^(+)CD45RA^(+)CCR7^(+)T lymphocyte subset in suitable donors that was significantly correlated with lower incidence of aGVHD and post-transplant anti-infection.The anti-aGVHD activity of this subset was confirmed in a validation cohort(n=30).Single-cell RNA sequencing revealed that this T cell subset exhibited transcriptomic features of stem cell-like memory T cell(TSCM)with both Treg and Teff activities which indicated its dual functions in aGVHD inhibition and graft-versus-leukemia(GVL)effect.Intriguingly,upon G-CSF mobilization,the donor PD-1^(+)CD8^(+)TSCM-like regulatory cells increased the PD-1 expression in a BCL6-dependent manner.Next,we showed that the mouse counterpart of this subset(PD-1^(+)CD8^(+)CD44^(-)CD62L^(+))ameliorated aGVHD,and confirmed the existence of this subset in clinical recipients.In summary,we,for the first time,identified a novel donor peripheral T cell subset suppressing aGVHD while promoting the immune reconstitution of recipients.It may serve as an indicator for optimal haploidentical and identical donor selection.Importantly,the dual Treg and Teff function of these T cells makes it a promising treatment for not only aGVHD but also auto-immune diseases.
文摘目的探讨HIV-1感染者慢性期治疗前后CD8^＋Tscm（stem memory Tcell）的特点及其与疾病进展的相关性。方法选取36例HIV-1慢性期感染者和20名健康对照者。用流式细胞术检测健康对照者和HIV-1感染者抗病毒治疗前后CD8^＋Tscm的比例和数量。分析CD8^＋Tscm与其他CD8^＋T细胞亚群和疾病进展指标（CIM^＋T细胞数量、病毒载量和T细胞活化水平）的相关性。结果抗病毒治疗前后，HIV-1慢性期感染者CD8^＋Tscm的比例和数量均无显著性变化。HIV-1慢性期感染者CD8^＋Tscm的比例和数量均与CIM^＋Tscm的比例和数量呈正相关性。CD8^＋Tscm的比例与CD8^＋Tcm（central memory T cell）的比例成正比．与CD8^＋Tern（effector memory T cell）的比例成反比。此外，在抗病毒治疗前，HIV-1慢性期感染者CD8^＋Tscm的比例与病毒载量呈负相关。结论CD8^＋Tscm参与维持其他CD8^＋T细胞亚群的稳态：CD8^＋Tscm参与抑制病毒的复制。
