Dataset Information

Human T Cell Differentiation Negatively Regulates Telomerase Expression Resulting in Reduced Activation-Induced Proliferation and Survival.

ABSTRACT: Maintenance of telomeres is essential for preserving T cell proliferative responses yet the precise role of telomerase in human T cell differentiation, function, and aging is not fully understood. Here we analyzed human telomerase reverse transcriptase (hTERT) expression and telomerase activity in six T cell subsets from 111 human adults and found that levels of hTERT mRNA and telomerase activity had an ordered decrease from naïve (TN) to central memory (TCM) to effector memory (TEM) cells and were higher in CD4+ than their corresponding CD8+ subsets. This differentiation-related reduction of hTERT mRNA and telomerase activity was preserved after activation. Furthermore, the levels of hTERT mRNA and telomerase activity were positively correlated with the degree of activation-induced proliferation and survival of T cells in vitro. Partial knockdown of hTERT by an anti-sense oligo in naïve CD4+ cells led to a modest but significant reduction of cell proliferation. Finally, we found that activation-induced levels of telomerase activity in CD4+ TN and TCM cells were significantly lower in old than in young subjects. These findings reveal that hTERT/telomerase expression progressively declines during T cell differentiation and age-associated reduction of activation-induced expression of hTERT/telomerase mainly affects naïve CD4+ T cells and suggest that enhancing telomerase activity could be a strategy to improve T cell function in the elderly.

SUBMITTER: Patrick MS

PROVIDER: S-EPMC6712505 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Human T Cell Differentiation Negatively Regulates Telomerase Expression Resulting in Reduced Activation-Induced Proliferation and Survival.

Patrick Michael S MS Cheng Nai-Lin NL Kim Jaekwan J An Jie J Dong Fangyuan F Yang Qian Q Zou Iris I Weng Nan-Ping NP

Frontiers in immunology 20190821

Maintenance of telomeres is essential for preserving T cell proliferative responses yet the precise role of telomerase in human T cell differentiation, function, and aging is not fully understood. Here we analyzed human telomerase reverse transcriptase (hTERT) expression and telomerase activity in six T cell subsets from 111 human adults and found that levels of hTERT mRNA and telomerase activity had an ordered decrease from naïve (T<sub>N</sub>) to central memory (T<sub>CM</sub>) to effector me ...[more]

PMID: 31497023

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Project description:BackgroundPersistent inflammation dysregulation and cognitive decline have been associated with several trauma- and stress-related disorders such as posttraumatic stress disorder (PTSD) and anxiety disorder. Despite the abundant discoveries of neuroinflammation in such disorders, the underlying mechanisms still remain unclear.MethodWild-type and Nlrp3-/- mice were exposed to the electric foot shocks in the contextual fear memory paradigm. Three hours after the electric foot shocks, activation of the NLRP3 inflammasome was investigated through immunoblotting and ELISA. Microglia were isolated and analyzed by quantitative real-time PCR. Hippocampal tissues were collected 3 h and 72 h after the electric foot shocks and subjected to RNA sequencing. MCC950 was administrated to mice via intraperitoneal (i.p.) injection. Interleukin-1 receptor antagonist (IL-ra) and interleukin-1β (IL-1β) were delivered via intracerebroventricular (i.c.v.) infusion. Contextual fear responses of mice were tested on 4 consecutive days (test days 1-4) starting at 48 h after the electric foot shocks. Anxiety-like behaviors were examined by elevated plus maze and open-field test.ResultsWe demonstrated that, in the contextual fear memory paradigm, the NLRP3 inflammasome was activated 3 h after electric foot shocks. We also found an upregulation in toll-like receptor and RIG-I-like receptor signaling, and a decrease in postsynaptic density (PSD) related proteins, such as PSD95 and Shank proteins, in the hippocampus 72 h after the electric foot shocks, indicating an association between neuroinflammation and PSD protein loss after stress encounter. Meanwhile, Nlrp3 knockout could significantly prevent both neuroinflammation and loss of PSD-related proteins, suggesting a possible protective role of NLRP3 deletion during this process. For further studies, we demonstrated that both genetic knockout and pharmaceutical inhibition of the NLRP3 inflammasome remarkably enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior caused by electric foot shocks. Moreover, cytokine IL-1β administration inhibited the extinction of contextual fear memory. Meanwhile, IL-1ra significantly enhanced the extinction of contextual fear memory and attenuated anxiety-like behavior.ConclusionTaken together, our data revealed the pivotal role of NLRP3 inflammasome activation in the regulation of fear memory and the development of PTSD and anxiety disorder, providing a novel target for the clinical treatment of such disorders.

Dataset Information

Human T Cell Differentiation Negatively Regulates Telomerase Expression Resulting in Reduced Activation-Induced Proliferation and Survival.

Publications

Human T Cell Differentiation Negatively Regulates Telomerase Expression Resulting in Reduced Activation-Induced Proliferation and Survival.

Similar Datasets

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