Role of Telomere and telomerase In Human Lymphocyte Function and Aging

端粒和端粒酶在人类淋巴细胞功能和衰老中的作用

• 批准号: 10913140
• 负责人: Nan-ping Peter Weng
• 金额: $ 31.34万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913140
• 关键词: Adult; Age; Aging; B-Lymphocytes; Blood Cells; CD28 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Aging; Cell Cycle; Cell Cycle Progression; Cell Senescence Induction; Cell division; Cell physiology; Cells; Cultured Cells; Cytomegalovirus; Cytomegalovirus Infections; Elderly; Epitopes; Gene Expression; Goals; Human; Immune System Diseases; Immune response; Immunoglobulin G; In Vitro; Individual; Influenza A virus; Length; Lymphocyte; Lymphocyte Function; MAP Kinase Gene; Measurement; Measures; Memory; Methods; Molecular; Mus; Phosphorylation; Process; Proliferating; Records; Reporter; Role; Serum; Signal Transduction; T memory cell; T-Lymphocyte; Telomerase; Telomere Shortening; Testing; in vivo; influenza virus vaccine; middle age; monocyte; mouse model; telomere

Cytomegalovirus (CMV) infection leads to effector memory CD8+ T cell expansion, shortened telomere length, and is associated with immune dysfunction in old humans. However, the molecular alterations of CMV-specific CD8+ T cells in CMV infected healthy young and middle-aged adults has not been fully understood. We compared CD8+ T cells specific for a CMV epitope (pp65495-503) and an influenza A virus (IAV) epitope (M158-66) from the same healthy adults with serum positive for anti-CMV IgG. Compared to the IAV-specific CD8+ T cells, CMV-specific CD8+ T cells were more differentiated and had a reduced activation-induced expansion in vitro, particularly central memory (TCM) but not nave (TN) cells. Furthermore, we found that CD70 expression was reduced in CMV-specific CD28+CD8+ TCM and that CD70+ TCM had better expansion in vitro than did CD70- TCM. Mechanistically, we demonstrated that CD70 directly enhanced MAPK phosphorylation and CMV-specific CD8+ TCM cells reduced MAPK signaling upon activation. Lastly, we showed that age did not exacerbate reduced CD70 expression in CMV- specific CD8+ TCM cells. Our findings demonstrated that CMV infection causes mild CD8+ T cell expansion, reduced CD70 expression and signaling, and proliferation of CMV-specific CD28+CD8+ TCM cells in young and middle-aged healthy adults and revealed an age-independent and CMV infection-specific impact on CD8+ memory T cells. Telomere length records past cell divisions and predicts the cellular replicative potential. The underlying mechanisms of short telomere-induced cell senescence are largely supported by culture cells and genetically modified mouse models. The cell cycle is a tightly controlled process. CDKN2a (p16) and CDKN1a (p21) are key regulators of cell cycle progression, and their expressions significantly increase in human T cells with age. However, it is not fully understood how shorter telomeres in a T cell triggers cessation of cell cycle or what regulates p16 or p21 expressions in shorter telomere T cells. Lack of functional measurement of short telomere lymphocytes impedes the precise interpreting of the roles of the telomere, p16, and p21 in T cells. Here we plan to use a new method we developed to measure telomere length and p16 and p21 levels in individual T cells, apply scRNAseq to identify gene expression changes in p16/p21 expressing T cells, and test the proliferation limit of T cells with short telomere in Tert KO/p16 or p21 reporter mice. Our study will provide evidence of the functional changes in short telomere, p16 and p21 expressing T cells and may explain telomere in T cell function, cellular senescence, and aging.

巨细胞病毒（CMV）感染导致效应记忆CD 8 + T细胞扩增，端粒长度缩短，并与老年人的免疫功能障碍有关。然而，CMV感染的健康青年和中年成人中CMV特异性CD 8 + T细胞的分子改变尚未完全了解。我们比较了来自抗CMV IgG阳性血清的相同健康成人的CMV表位（pp 65495 -503）和甲型流感病毒（IAV）表位（M158-66）特异性CD 8 + T细胞。与IAV特异性CD 8 + T细胞相比，CMV特异性CD 8 + T细胞在体外分化程度更高，活化诱导的扩增减少，特别是中央记忆（TCM）细胞，而不是幼稚（TN）细胞。此外，我们还发现CMV特异性CD 28 + CD 8 + TCM中CD 70表达降低，并且CD 70 + TCM比CD 70- TCM具有更好的体外扩增。从机制上讲，我们证明了CD 70直接增强MAPK磷酸化，CMV特异性CD 8 + TCM细胞在活化后减少MAPK信号传导。最后，我们发现年龄并没有加剧CMV特异性CD 8 + TCM细胞中CD 70表达的降低。我们的研究结果表明，CMV感染导致轻度的CD 8 + T细胞扩增，CD 70表达和信号传导减少，以及年轻和中年健康成人中CMV特异性CD 28 + CD 8 + TCM细胞的增殖，并揭示了对CD 8+记忆T细胞的年龄无关性和CMV感染特异性影响。 端粒长度记录了过去的细胞分裂和预测细胞的复制潜力。短端粒诱导细胞衰老的潜在机制在很大程度上得到了培养细胞和遗传修饰小鼠模型的支持。细胞周期是一个严格控制的过程。CDKN 2a（p16）和CDKN 1a（p21）是细胞周期进程的关键调节因子，它们在人类T细胞中的表达随着年龄的增长而显著增加。然而，目前还不完全清楚T细胞中较短的端粒如何触发细胞周期的停止，或者是什么调节了较短端粒T细胞中p16或p21的表达。短端粒淋巴细胞功能测量的缺乏阻碍了端粒，p16和p21在T细胞中的作用的精确解释。 在这里，我们计划使用我们开发的一种新方法来测量单个T细胞中的端粒长度和p16和p21水平，应用scRNAseq来鉴定表达p16/p21的T细胞中的基因表达变化，并测试Tert KO/p16或p21报告小鼠中具有短端粒的T细胞的增殖极限。我们的研究将提供短端粒，p16和p21表达T细胞的功能变化的证据，并可能解释端粒在T细胞功能，细胞衰老和老化。

项目成果

Sex differences in the association between antinuclear antibody positivity with diabetes and multimorbidity in older adults: Results from the Baltimore Longitudinal Study of Aging.

老年人抗核抗体阳性与糖尿病和多重发病之间关联的性别差异：巴尔的摩老龄化纵向研究的结果。

• DOI: 10.1016/j.exger.2020.110906
• 发表时间: 2020
• 期刊: Experimental gerontology
• 影响因子: 3.9
• 作者: Meier,HelenCS;Sandler,DaleP;Simonsick,EleanorM;Weng,Nan-Ping;Parks,ChristineG
• 通讯作者: Parks,ChristineG

Changes in blood lymphocyte numbers with age in vivo and their association with the levels of cytokines/cytokine receptors.

• DOI: 10.1186/s12979-016-0079-7
• 发表时间: 2016
• 期刊: Immunity & ageing : I & A
• 作者: Lin Y;Kim J;Metter EJ;Nguyen H;Truong T;Lustig A;Ferrucci L;Weng NP
• 通讯作者: Weng NP

Long term effects of radiation exposure on telomere lengths of leukocytes and its associated biomarkers among atomic-bomb survivors.

• DOI: 10.18632/oncotarget.8801
• 发表时间: 2016-06-28
• 期刊: Oncotarget
• 作者: Lustig A;Shterev I;Geyer S;Shi A;Hu Y;Morishita Y;Nagamura H;Sasaki K;Maki M;Hayashi I;Furukawa K;Yoshida K;Kajimura J;Kyoizumi S;Kusunoki Y;Ohishi W;Nakachi K;Weng NP;Hayashi T
• 通讯作者: Hayashi T

Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors.

• DOI: 10.1016/j.mrgentox.2016.04.006
• 发表时间: 2016-05
• 期刊: MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
• 影响因子: 1.9
• 作者: Kajimura, Junko;Kyoizumi, Seishi;Kubo, Yoshiko;Misumi, Munechika;Yoshida, Kengo;Hayashi, Tomonori;Imai, Kazue;Ohishi, Waka;Nakachi, Kei;Weng, Nan-ping;Young, Lauren F.;Shieh, Jae-Hung;Moore, Malcolm A.;van den Brink, Marcel R. M.;Kusunoki, Yoichiro
• 通讯作者: Kusunoki, Yoichiro

Corrigendum to "Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors" [Mutat. Res. - Genet. Toxicol. Environ. Mutagen. 802 (2016) 59-65].

勘误表“原子弹幸存者循环造血干细胞和祖细胞中自发γH2AX病灶形成与祖细胞功能之间的关系”[Mutat。

• DOI: 10.1016/j.mrgentox.2017.11.003
• 发表时间: 2018
• 期刊: Mutation research. Genetic toxicology and environmental mutagenesis
• 作者: Kajimura,Junko;Kyoizumi,Seishi;Kubo,Yoshiko;Misumi,Munechika;Yoshida,Kengo;Hayashi,Tomonori;Imai,Kazue;Ohishi,Waka;Nakachi,Kei;Weng,Nan-Ping;Young,LaurenF;Shieh,Jae-Hung;Moore,MalcolmA;vandenBrink,MarcelRM;Kusunoki,Yoich
• 通讯作者: Kusunoki,Yoich