Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling a...Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.展开更多
多年来,肿瘤进展位点2(tumor progression locus 2,TPL2)被认为是免疫反应的重要调节器,向下游的效应分子传递炎性信号,进而调节炎性细胞因子的生成和功能。TPL2在多种肿瘤中也有差异表达和激活,与肿瘤相关炎症增加、恶性转化、血管生...多年来,肿瘤进展位点2(tumor progression locus 2,TPL2)被认为是免疫反应的重要调节器,向下游的效应分子传递炎性信号,进而调节炎性细胞因子的生成和功能。TPL2在多种肿瘤中也有差异表达和激活,与肿瘤相关炎症增加、恶性转化、血管生成和转移有关。然而,TPL2驱动的肿瘤相关炎症、肿瘤发生和免疫之间的关系尚不明确。因此本文综述了TPL2在促肿瘤炎症、肿瘤发生和免疫中的作用,并强调了TPL2适配器功能在肿瘤发生中的潜在功能以及靶向TPL2用于治疗肿瘤的意义,可能有助于开发更具综合性和特异性的抗炎和抗肿瘤疗法。展开更多
TPL2(tumor progression locus 2)为一种激酶,虽然最初是作为一种致癌基因被发现,但其在机体的炎症反应中也起重要作用。TPL2激酶可通过丝裂原激活蛋白激酶信号转导通路,介导多种细胞因子的信号转导,影响炎症反应和免疫过程的多个环节,...TPL2(tumor progression locus 2)为一种激酶,虽然最初是作为一种致癌基因被发现,但其在机体的炎症反应中也起重要作用。TPL2激酶可通过丝裂原激活蛋白激酶信号转导通路,介导多种细胞因子的信号转导,影响炎症反应和免疫过程的多个环节,参与多种炎症性相关疾病的发生。炎症性肠病(IBD)作为一种以肠道慢性炎症反应为特征的免疫性疾病,目前尚未有治愈药物。近年来,随着对IBD发病机制研究的不断深入,越来越多的相关发病因子、小分子抑制剂的研发备受关注。TPL2激酶通过其在炎症反应过程的作用,参与IBD的发病。未来,TPL2激酶可能成为IBD治疗药物研究的潜在靶点。展开更多
通过基因合成的TPL2(tumor progression locus 2)质粒,获得稳定表达TPL2的PK-15/TPL2细胞系。将慢病毒载体Lv-PCDH和TPL2(Pig)重组慢病毒载体Lv-TPL2(Pig)利用转染试剂将其转染至PK-15细胞。感染48 h后,加入嘌呤霉素进行药物筛选,通过...通过基因合成的TPL2(tumor progression locus 2)质粒,获得稳定表达TPL2的PK-15/TPL2细胞系。将慢病毒载体Lv-PCDH和TPL2(Pig)重组慢病毒载体Lv-TPL2(Pig)利用转染试剂将其转染至PK-15细胞。感染48 h后,加入嘌呤霉素进行药物筛选,通过筛选得到的阳性细胞株PK-15/TPL2即为稳定表达TPL2蛋白的PK-15细胞株。通过qRT-PCR法和琼脂糖凝胶电泳、IFA,TCID50技术验证PK-15/TPL2细胞系和对口蹄疫病毒(foot-and-mouth disease virus,FMDV)和猪塞内加谷病毒(seneca valley virus,SVV)病原复制的影响。结果显示,细胞表达大量的TPL2的基因产物,用FMDV、SVV病毒感染稳定表达TPL2的PK-15细胞株时,明显抑制病毒的复制。结果表明,利用该技术可高效快速地建立了稳定高表达TPL2的PK-15细胞系,该细胞株的建立为病毒的分离及TPL2的生物学活性研究奠定理论基础。展开更多
基金This study was supported by grants from the National Institutes of Health(AI64639 and GM84459)the core facilities of MD Anderson Cancer Center are supported by the NIH/NCI Cancer Center Support Grant(CCSG)P30CA016672.
文摘Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.
文摘多年来,肿瘤进展位点2(tumor progression locus 2,TPL2)被认为是免疫反应的重要调节器,向下游的效应分子传递炎性信号,进而调节炎性细胞因子的生成和功能。TPL2在多种肿瘤中也有差异表达和激活,与肿瘤相关炎症增加、恶性转化、血管生成和转移有关。然而,TPL2驱动的肿瘤相关炎症、肿瘤发生和免疫之间的关系尚不明确。因此本文综述了TPL2在促肿瘤炎症、肿瘤发生和免疫中的作用,并强调了TPL2适配器功能在肿瘤发生中的潜在功能以及靶向TPL2用于治疗肿瘤的意义,可能有助于开发更具综合性和特异性的抗炎和抗肿瘤疗法。
文摘TPL2(tumor progression locus 2)为一种激酶,虽然最初是作为一种致癌基因被发现,但其在机体的炎症反应中也起重要作用。TPL2激酶可通过丝裂原激活蛋白激酶信号转导通路,介导多种细胞因子的信号转导,影响炎症反应和免疫过程的多个环节,参与多种炎症性相关疾病的发生。炎症性肠病(IBD)作为一种以肠道慢性炎症反应为特征的免疫性疾病,目前尚未有治愈药物。近年来,随着对IBD发病机制研究的不断深入,越来越多的相关发病因子、小分子抑制剂的研发备受关注。TPL2激酶通过其在炎症反应过程的作用,参与IBD的发病。未来,TPL2激酶可能成为IBD治疗药物研究的潜在靶点。
文摘通过基因合成的TPL2(tumor progression locus 2)质粒,获得稳定表达TPL2的PK-15/TPL2细胞系。将慢病毒载体Lv-PCDH和TPL2(Pig)重组慢病毒载体Lv-TPL2(Pig)利用转染试剂将其转染至PK-15细胞。感染48 h后,加入嘌呤霉素进行药物筛选,通过筛选得到的阳性细胞株PK-15/TPL2即为稳定表达TPL2蛋白的PK-15细胞株。通过qRT-PCR法和琼脂糖凝胶电泳、IFA,TCID50技术验证PK-15/TPL2细胞系和对口蹄疫病毒(foot-and-mouth disease virus,FMDV)和猪塞内加谷病毒(seneca valley virus,SVV)病原复制的影响。结果显示,细胞表达大量的TPL2的基因产物,用FMDV、SVV病毒感染稳定表达TPL2的PK-15细胞株时,明显抑制病毒的复制。结果表明,利用该技术可高效快速地建立了稳定高表达TPL2的PK-15细胞系,该细胞株的建立为病毒的分离及TPL2的生物学活性研究奠定理论基础。
