Stem cell-like memory T(TSCM)cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases.Advanced technologies such as multiparamet...Stem cell-like memory T(TSCM)cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases.Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization.In case of chronic viral diseases such as human immunodeficiency virus-1,CD4+T_(SCM) cells,serve as major reservoirs of the latent virus.However,during immune activation and functional exhaustion of effector T cells,these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection.More recently,these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion.Similarly,studies are also investigating their pathological role in driving autoimmune responses.However,there are several gaps in the understanding of the role of T_(SCM) cells in viral and autoimmune diseases to make them potential therapeutic targets.In this minireview,we have attempted an updated compilation of the dyadic role of these complex T_(SCM) cells during such human diseases along with their biology and transcriptional programs.展开更多
Objective: Memory stem T cells(Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear c...Objective: Memory stem T cells(Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear cell carcinoma(RCC) and the role of Wnt signaling in these cells. We evaluated Tscm from RCC patients concerning their activation of Wnt signaling in vitro and explored the mechanism of preferential survival.Methods: Flow cytometry identified surface markers and cytokines produced from accumulated Tscm in the presence of the glycogen synthase kinase beta inhibitor TWS119. Apoptosis was evaluated after induction using tumor necrosis factor-alpha.Immunofluorescence and Western blot analyses were used to investigate the activation of the nuclear factor-kappa B(NF-КB)pathway.Results: RCC patients had a similar percentage of CD4^+ and CD8^+ Tscm as healthy donors. Activation of Wnt signaling by TWS119 resulted in the accumulation of Tscm in activated T cells, but reversal of differentiated T cells to Tscm was not achieved.Preferential survival of Tscm was associated with increased anti-apoptotic ability mediated downstream of the NF-КB activation pathway.Conclusions: The finding that Tscm can accumulate by Wnt signaling in vitro in blood from RCC patients will help in devising new cancer therapy strategies of Tscm-based adoptive immunotherapy, such as dendritic cell-stimulated Tscm, and T cell receptor or chimeric antigen receptor-engineered Tscm.展开更多
When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that ar...When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that are the major drivers of graft-vs-host disease(Gv HD). The risk for Gv HD can simply be reduced by the removal of these T cells from the graft. However, this is not always desirable, as this procedure also decreases the engraftment of the transplanted HSPCs and, if applicable, a graft-vs-tumor effect. This poses an important conundrum in the field: T cells act as a double-edged sword upon allogeneic HSPC transplantation, as they support engraftment of HSPCs and provide anti-tumor activity, but can also cause Gv HD. It has recently been suggested that T cells also enhance the engraftment of autologous HSPCs, thus supporting the notion that T cells and HSPCs have an important functional interaction that is highly beneficial, in particular during transplantation. The underlying reason on why and how T cells contribute to HSPC engraftment is still poorly understood. Therefore, we evaluate in this review the studies that have examined the role of T cells during HSPC transplantation and the possible mechanisms involved in their supporting function. Understanding the underlying cellular and molecular mechanisms can provide new insight into improving HSPC engraftment and thus lower the number of HSPCs required during transplantation. Moreover, it could provide new avenues to limit the development of severe Gv HD, thus making HSPC transplantations more efficient and ultimately safer.展开更多
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
记忆性干细胞样T细胞(stem memory T cells,TSCM)是最近几年发现的一个细胞亚群,约占外周血中总的CD4+T细胞和CD8+T细胞的2%~4%,是记忆性T细胞的早期分化阶段,具有记忆性细胞和干细胞的特点,基因谱介于初始T细胞和中央记忆T细胞之间。...记忆性干细胞样T细胞(stem memory T cells,TSCM)是最近几年发现的一个细胞亚群,约占外周血中总的CD4+T细胞和CD8+T细胞的2%~4%,是记忆性T细胞的早期分化阶段,具有记忆性细胞和干细胞的特点,基因谱介于初始T细胞和中央记忆T细胞之间。记忆性干细胞样T细胞具有自我更新和长期存活能力,这些特点使它们成为肿瘤领域关注的热点。本文将简述记忆性干细胞样T细胞的一些特点,以及它们在肿瘤治疗中的应用。展开更多
目的:探讨生长分化因子11(GDF11)在体外诱导扩增具有干细胞特性的记忆性T细胞(memory stem T cells,Tscm)中的作用,从而进一步提高免疫过继治疗的疗效。方法:通过密度梯度离心的方法分离健康人的外周血单个核细胞,然后用磁珠分选获得CD8...目的:探讨生长分化因子11(GDF11)在体外诱导扩增具有干细胞特性的记忆性T细胞(memory stem T cells,Tscm)中的作用,从而进一步提高免疫过继治疗的疗效。方法:通过密度梯度离心的方法分离健康人的外周血单个核细胞,然后用磁珠分选获得CD8^+T细胞;随后将所得的细胞分为实验组和对照组,实验组中加入等体积、不同浓度的GDF11,对照组中加入等体积的PBS缓冲液,最后分别在不同时点通过流式细胞术检测2组细胞中Tscm的扩增情况。结果:在CD8^+T细胞的体外扩增实验中,GDF11可以显著扩增CD8^+T细胞;在CD8^+T细胞的体外培养实验中,GDF11可以显著提高Tscm在CD8^+T细胞中的比例。结论:GDF11可以有效地在体外扩增CD8^+Tscm,为提高免疫过继治疗的效率提供了新的方法。展开更多
记忆性干细胞样T细胞(stem cell-like memory T cells,T_(SCM))是近期发现的一群具有自我更新、长期生存以及分化为其他类型T细胞的多能干细胞。这些特性使其正成为细胞免疫治疗的重要武器。但是,由于正常人体内的T_(SCM)极为稀少,这成...记忆性干细胞样T细胞(stem cell-like memory T cells,T_(SCM))是近期发现的一群具有自我更新、长期生存以及分化为其他类型T细胞的多能干细胞。这些特性使其正成为细胞免疫治疗的重要武器。但是,由于正常人体内的T_(SCM)极为稀少,这成为其临床转化应用的绊脚石。近年来,越来越多的研究发现通过调控WNT、m TORC、Notch等信号通路可以促进T_(SCM)的产生。通过小分子药物调控相关信号通路可以诱导、促进多能干细胞的转化。同时,细胞因子以及APC在T_(SCM)细胞的产生上也扮演着至关重要的角色。本文主要聚焦通过小分子药物、细胞因子等调控相关信号通路获取T_(SCM)机制的研究进展。展开更多
目的研究肾癌患者外周血干细胞样记忆性T细胞(stem-like memory T cells,TSCM)的分布特征,探讨TSCM与临床病理特征的关系。方法选取2019年1月~2020年3月连云港第一人民医院收治的65例肾癌患者为肾癌组,同期30例健康志愿者为健康组。运...目的研究肾癌患者外周血干细胞样记忆性T细胞(stem-like memory T cells,TSCM)的分布特征,探讨TSCM与临床病理特征的关系。方法选取2019年1月~2020年3月连云港第一人民医院收治的65例肾癌患者为肾癌组,同期30例健康志愿者为健康组。运用流式细胞术检测两组患者外周血中初始T细胞(naive T cells,TN)和TSCM比例,比较肾癌组与健康组的差异,分析TSCM、TN和TSCM/TN值与临床病理特征的关系。结果与健康组比较,肾癌组患者外周血TSCM比例(0.15%±0.06%vs 0.20%±0.11%,t=2.524,P<0.05)和TN比例(2.66%±1.18%vs 6.29%±1.58%,t=12.499,P<0.01)均明显降低,TSCM/TN值(6.48%±3.70%vs 3.31%±1.82%,t=5.600,P<0.01)明显升高。肾癌患者中,TSCM比例与肿瘤TNM分期(r=-0.258,P<0.05)和Fuhrman核分级(r=-0.271,P<0.05)呈负相关;TN比例与肿瘤TNM分期(r=-0.447,P<0.01)和Fuhrman核分级(r=-0.263,P<0.05)呈负相关;TSCM/TN值与肿瘤TNM分期(r=0.433,P<0.01)呈正相关。结论肾癌患者外周血TSCM、TN及TSCM/TN值与肿瘤TNM分期和Fuhrman核分级密切相关,可用于评估肿瘤发生、发展情况,TSCM在肾癌的过继性免疫治疗中具有广阔的应用前景。展开更多
干细胞样记忆型T细胞(Stem memory T cells,Tscm)是最早期分化的、存活时间最长的一类记忆型T细胞。这类细胞具有自我更新及多能分化等干细胞特性,其在抗肿瘤中具有重要的作用,在HIV-1感染中的作用也开始成为研究热点。本文对Tscm细胞...干细胞样记忆型T细胞(Stem memory T cells,Tscm)是最早期分化的、存活时间最长的一类记忆型T细胞。这类细胞具有自我更新及多能分化等干细胞特性,其在抗肿瘤中具有重要的作用,在HIV-1感染中的作用也开始成为研究热点。本文对Tscm细胞的特点、CD4+Tscm细胞在HIV-1病毒储藏库中的重要性及CD8+Tscm细胞抗病毒作用的最新研究进行介绍。了解并充分利用Tscm细胞的特性及其在HIV-1感染中的作用,将有助于开发以Tscm为靶点的HIV-1疫苗及免疫治疗新方法,为HIV-1的防控及功能性治愈提供新的策略。展开更多
文摘Stem cell-like memory T(TSCM)cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases.Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization.In case of chronic viral diseases such as human immunodeficiency virus-1,CD4+T_(SCM) cells,serve as major reservoirs of the latent virus.However,during immune activation and functional exhaustion of effector T cells,these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection.More recently,these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion.Similarly,studies are also investigating their pathological role in driving autoimmune responses.However,there are several gaps in the understanding of the role of T_(SCM) cells in viral and autoimmune diseases to make them potential therapeutic targets.In this minireview,we have attempted an updated compilation of the dyadic role of these complex T_(SCM) cells during such human diseases along with their biology and transcriptional programs.
基金supported by grants from the National Science and Technology Support Project (Grant No. 2015BAI12B12)the National Natural Science Foundation of China (Grant No. 81401887)+1 种基金the National Natural Science Foundation of China (Grant No. 81470293)the Tianjin Natural Science Foundation (Grant No. 14JCQNJC11500)
文摘Objective: Memory stem T cells(Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear cell carcinoma(RCC) and the role of Wnt signaling in these cells. We evaluated Tscm from RCC patients concerning their activation of Wnt signaling in vitro and explored the mechanism of preferential survival.Methods: Flow cytometry identified surface markers and cytokines produced from accumulated Tscm in the presence of the glycogen synthase kinase beta inhibitor TWS119. Apoptosis was evaluated after induction using tumor necrosis factor-alpha.Immunofluorescence and Western blot analyses were used to investigate the activation of the nuclear factor-kappa B(NF-КB)pathway.Results: RCC patients had a similar percentage of CD4^+ and CD8^+ Tscm as healthy donors. Activation of Wnt signaling by TWS119 resulted in the accumulation of Tscm in activated T cells, but reversal of differentiated T cells to Tscm was not achieved.Preferential survival of Tscm was associated with increased anti-apoptotic ability mediated downstream of the NF-КB activation pathway.Conclusions: The finding that Tscm can accumulate by Wnt signaling in vitro in blood from RCC patients will help in devising new cancer therapy strategies of Tscm-based adoptive immunotherapy, such as dendritic cell-stimulated Tscm, and T cell receptor or chimeric antigen receptor-engineered Tscm.
基金Supported by a fellowship obt-ained by Nolt-e MA from t-he Landst-einer Foundat-ion for Blood Transfusion Research(www.lsbr.nl),No.#1014
文摘When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that are the major drivers of graft-vs-host disease(Gv HD). The risk for Gv HD can simply be reduced by the removal of these T cells from the graft. However, this is not always desirable, as this procedure also decreases the engraftment of the transplanted HSPCs and, if applicable, a graft-vs-tumor effect. This poses an important conundrum in the field: T cells act as a double-edged sword upon allogeneic HSPC transplantation, as they support engraftment of HSPCs and provide anti-tumor activity, but can also cause Gv HD. It has recently been suggested that T cells also enhance the engraftment of autologous HSPCs, thus supporting the notion that T cells and HSPCs have an important functional interaction that is highly beneficial, in particular during transplantation. The underlying reason on why and how T cells contribute to HSPC engraftment is still poorly understood. Therefore, we evaluate in this review the studies that have examined the role of T cells during HSPC transplantation and the possible mechanisms involved in their supporting function. Understanding the underlying cellular and molecular mechanisms can provide new insight into improving HSPC engraftment and thus lower the number of HSPCs required during transplantation. Moreover, it could provide new avenues to limit the development of severe Gv HD, thus making HSPC transplantations more efficient and ultimately safer.
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。
文摘记忆性干细胞样T细胞(stem memory T cells,TSCM)是最近几年发现的一个细胞亚群,约占外周血中总的CD4+T细胞和CD8+T细胞的2%~4%,是记忆性T细胞的早期分化阶段,具有记忆性细胞和干细胞的特点,基因谱介于初始T细胞和中央记忆T细胞之间。记忆性干细胞样T细胞具有自我更新和长期存活能力,这些特点使它们成为肿瘤领域关注的热点。本文将简述记忆性干细胞样T细胞的一些特点,以及它们在肿瘤治疗中的应用。
文摘目的:探讨生长分化因子11(GDF11)在体外诱导扩增具有干细胞特性的记忆性T细胞(memory stem T cells,Tscm)中的作用,从而进一步提高免疫过继治疗的疗效。方法:通过密度梯度离心的方法分离健康人的外周血单个核细胞,然后用磁珠分选获得CD8^+T细胞;随后将所得的细胞分为实验组和对照组,实验组中加入等体积、不同浓度的GDF11,对照组中加入等体积的PBS缓冲液,最后分别在不同时点通过流式细胞术检测2组细胞中Tscm的扩增情况。结果:在CD8^+T细胞的体外扩增实验中,GDF11可以显著扩增CD8^+T细胞;在CD8^+T细胞的体外培养实验中,GDF11可以显著提高Tscm在CD8^+T细胞中的比例。结论:GDF11可以有效地在体外扩增CD8^+Tscm,为提高免疫过继治疗的效率提供了新的方法。
文摘目的研究肾癌患者外周血干细胞样记忆性T细胞(stem-like memory T cells,TSCM)的分布特征,探讨TSCM与临床病理特征的关系。方法选取2019年1月~2020年3月连云港第一人民医院收治的65例肾癌患者为肾癌组,同期30例健康志愿者为健康组。运用流式细胞术检测两组患者外周血中初始T细胞(naive T cells,TN)和TSCM比例,比较肾癌组与健康组的差异,分析TSCM、TN和TSCM/TN值与临床病理特征的关系。结果与健康组比较,肾癌组患者外周血TSCM比例(0.15%±0.06%vs 0.20%±0.11%,t=2.524,P<0.05)和TN比例(2.66%±1.18%vs 6.29%±1.58%,t=12.499,P<0.01)均明显降低,TSCM/TN值(6.48%±3.70%vs 3.31%±1.82%,t=5.600,P<0.01)明显升高。肾癌患者中,TSCM比例与肿瘤TNM分期(r=-0.258,P<0.05)和Fuhrman核分级(r=-0.271,P<0.05)呈负相关;TN比例与肿瘤TNM分期(r=-0.447,P<0.01)和Fuhrman核分级(r=-0.263,P<0.05)呈负相关;TSCM/TN值与肿瘤TNM分期(r=0.433,P<0.01)呈正相关。结论肾癌患者外周血TSCM、TN及TSCM/TN值与肿瘤TNM分期和Fuhrman核分级密切相关,可用于评估肿瘤发生、发展情况,TSCM在肾癌的过继性免疫治疗中具有广阔的应用前景。
文摘干细胞样记忆型T细胞(Stem memory T cells,Tscm)是最早期分化的、存活时间最长的一类记忆型T细胞。这类细胞具有自我更新及多能分化等干细胞特性,其在抗肿瘤中具有重要的作用,在HIV-1感染中的作用也开始成为研究热点。本文对Tscm细胞的特点、CD4+Tscm细胞在HIV-1病毒储藏库中的重要性及CD8+Tscm细胞抗病毒作用的最新研究进行介绍。了解并充分利用Tscm细胞的特性及其在HIV-1感染中的作用,将有助于开发以Tscm为靶点的HIV-1疫苗及免疫治疗新方法,为HIV-1的防控及功能性治愈提供新的策略。
