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

Michael S Patrick,Qian Yang,Jaekwan Kim,Fangyuan Dong,Nan-Ping Weng,Jie An,Nai-Lin Cheng,Iris Zou

doi:10.3389/fimmu.2019.01993

Michael S Patrick, Qian Yang + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2019.01993

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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.

Highlights

T cell differentiation is an essential process for establishing long lasting immunity
These findings suggest that CD4+ and CD8+ T cells had intrinsically different set points of human telomerase reverse transcriptase (hTERT) expression levels and that T cell differentiation is associated with reduced expression of hTERT mRNA
We found that the levels of telomerase activity in activated T cells displayed the same order as hTERT mRNA levels in activated T cell subsets, namely, the highest level of telomerase activity was found in activated CD4+ TN cells and the lowest in activated CD8+ to effector memory (TEM) (Figure 1D) and the levels of hTERT mRNA and telomerase activity was positively correlated in a linear fashion (Figure 1E)

Summary

Introduction

T cell differentiation is an essential process for establishing long lasting immunity. During this process, naïve T cells differentiate into effector cells to combat pathogens and become memory T cells for long term protection [1]. As a consequence of differentiation, T cells acquire distinct, and specialized functions in each specific subset of differentiated T cells [2, 3]. Human CD4+ and CD8+ T cells in peripheral blood are composed of mainly naive (TN), central (TCM), and effector (TEM) memory T cells as defined by cell surface expression of CD62L/CCR7 and CD45RA [4]. Recent transcriptome analyses reveal distinct gene expression changes associated with human T cell differentiation and their functional specialization [7,8,9]. In contrast to welldocumented gain of function during T cell differentiation, loss of function during T cell differentiation has not been fully characterized

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