Abstract
T cells play a crucial role in viral clearance and vaccine responses; however, the mechanisms that regulate their homeostasis during viral infections remain unclear. In this study, we investigated the machineries of T-cell homeostasis and telomeric DNA damage using a human model of hepatitis C virus (HCV) infection. We found that naïve CD4 T cells in chronically HCV-infected patients (HCV T cells) were significantly reduced due to apoptosis compared with age-matched healthy subjects (HSs). These HCV T cells were not only senescent, as demonstrated by overexpression of aging markers and particularly shortened telomeres; but also DNA damaged, as evidenced by increased dysfunctional telomere-induced foci (TIF). Mechanistically, the telomere shelterin protein, in particular telomeric repeat binding factor 2 (TRF2) that functions to protect telomeres from DNA damage, was significantly inhibited posttranscriptionally via the p53-dependent Siah-1a ubiquitination. Importantly, knockdown of TRF2 in healthy T cells resulted in increases in telomeric DNA damage and T-cell apoptosis, whereas overexpression of TRF2 in HCV T cells alleviated telomeric DNA damage and T-cell apoptosis. To the best of our knowledge, this is the first report revealing that inhibition of TRF2 promotes T-cell telomere attrition and telomeric DNA damage that accelerates T-cell senescent and apoptotic programs, which contribute to naïve T-cell loss during viral infection. Thus, restoring the impaired T-cell telomeric shelterin machinery may offer a new strategy to improve immunotherapy and vaccine response against human viral diseases.
Highlights
T cells play a pivotal role in controlling viral infection and vaccine responses; the mechanisms underlying T-cell dysfunction that lead to chronic infection and poor vaccine response remain unclear
To identify factors that perturb T-cell homeostasis during viral infection, we have explored the role of telomeric repeat binding factor 2 (TRF2) in protecting telomeric DNA damage and T-cell apoptosis with a model of Hepatitis C virus (HCV) infection
As an initial approach to identify factors that perturb T-cell homeostasis in HCV infection, we first analyzed total CD4+, naïve CD4+CD45RA+, and memory CD4+CD45RA− T-cell subsets in Peripheral blood mononuclear cells (PBMCs) isolated from HCV and healthy subjects (HSs)
Summary
T cells play a pivotal role in controlling viral infection and vaccine responses; the mechanisms underlying T-cell dysfunction that lead to chronic infection and poor vaccine response remain unclear. Telomeres are repeating hexameric DNA sequences that are found at chromosome ends in association with a complex of shelterin proteins. Nguyen et al Cell Death and Disease (2018)9:900 the telomerase, shelterin is essential to protect telomeres against unwanted DNA damage response (DDR)[12,13]. Shelterin comprises six polypeptides (TRF1, TRF2, RAP1, TIN2, TPP1, and POT1), of which telomeric repeat binding factor 2 (TRF2) is a key factor that plays an essential role in maintaining telomere integrity[14]. The role of TRF2 in reprogramming telomeric DNA damage and remodeling T-cell homeostasis during viral infection, is largely unknown
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