Abstract
T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.
Highlights
T cells play a crucial role in defending the host against infections; the mechanisms controlling their responses to pathogenic infections remain incompletely understood
Senescent T cells are characterized by accelerated telomere erosion, which has two potential outcomes: cell cycle arrest or cell apoptosis
If telomere attrition is mild to moderate, it will trigger cell cycle arrest in order to give the cell a chance to repair the DNA damage; if the telomere loss reaches a critical point or DNA damage becomes irreparable, it will trigger programmed cell death to get rid of cells harboring unhealthy genetic transformations
Summary
T cells play a crucial role in defending the host against infections; the mechanisms controlling their responses to pathogenic infections remain incompletely understood. Telomeres are repeating hexameric DNA sequences (TTAGGG) that are found at the chromosome ends in association with a complex of shelterin proteins [14]. While telomere length is maintained in most cases by an enzyme called telomerase, the telomeric shelterin complex is required to protect telomeres from the undesired DNA damage response (DDR) [16,17,18,19]. The capping roles of this shelterin complex are to inhibit DDR pathways at telomeres, regulate telomerase access and functions, prevent telomeric DNA from degradation or erosion, and safeguard human chromosome ends [19]. Among the many mammalian telomeric shelterin proteins identified in the past decade, telomeric repeat binding factor 2 (TRF2) plays a crucial role in protecting chromosome ends against instability [20, 21]. The role and mechanisms of TRF2, telomerase, Top1/2α, and ATM in telomeric DNA damage and repair in T lymphocyte senescence remain elusive
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