Shelterin dysfunction promotes CD4+ T cell senescence in Behçet’s disease

Abstract

Objectives To investigate the potential role of shelterin dysfunction in naïve CD4+ T cells in the pathogenesis of Behçet's disease (BD). Methods Naïve CD4+ T cells were isolated from 40 BD patients and 40 sex- and age-matched healthy controls (HC). Senescent profiles, shelterin subunits expression, telomere length, telomerase activity, and critical DNA damage response (DDR) was evaluated. TRF2 silencing was conducted for further validation. Results Compared to HC, BD patients had significantly decreased naïve CD4+ T cells, increased cell apoptosis, senescence, and productions of TNF-α and IFN-γ upon activation. Notably, BD naïve CD4+ T cells had shortened telomere, impaired telomerase activity, and expressed lower levels of shelterin subunits TRF2, TIN2, and RAP1. Furthermore, BD naïve CD4+ T cells exhibited significantly increased DDR, evidenced by elevated phosphorylated ataxia telangiectasia (AT) mutated (pATM), pp53, and p21. Finally, TRF2-silencing markedly upregulated DDR, apoptosis, and proinflammatory cytokines production in HC naïve CD4+ T cells. Conclusion Our study demonstrated that TRF2 deficiency in BD naïve CD4+ T cells promoted cell apoptosis and senescence, leading to proinflammatory cytokines overproduction. Therefore, restoring TRF2 might be a promising therapeutic strategy for BD.

β-Cyclocitral from Lavandula angustifolia Mill. Exerts Anti-Aging Effects on Yeasts and Mammalian Cells via Telomere Protection, Antioxidative Stress, and Autophagy Activation

“…Telomerase activity and telomere length are closely associated with longevity [ 4 , 5 , 6 , 7 , 8 ]. In this study, we investigated the effect of CYC on telomerase and the telomere length in both yeast and mammalian cells.…”

“…To explore the signaling pathways through which CYC protects telomeres, we examined its effects on shelterin proteins such as TRF2 and RAP1 [ 4 , 7 , 8 ]. Western blot assays were conducted to assess changes in TRF2 and RAP1 protein expression in 3T3 cells following treatment with AST and CYC.…”

“…In vertebrates, these specialized proteins are referred to as shelterin proteins, with telomeric-repeat binding factor 2 (TRF2) and repressor activator protein 1 (RAP1) being essential components [ 4 ]. TRF2 directly binds to double-stranded telomeric repeats, and its deficiency promotes cellular senescence and apoptosis in patients with Behcet’s disease [ 7 ]. RAP1, on the other hand, is recruited to telomeres by TRF2 and protects against obesity and insulin resistance in mice [ 8 ].…”

“…RAP1, on the other hand, is recruited to telomeres by TRF2 and protects against obesity and insulin resistance in mice [ 8 ]. Previous studies have shown that adult mammalian tissues do not possess sufficient telomerase to maintain telomere length throughout the lifespan [ 3 , 4 , 5 , 6 , 7 , 8 ]. Therefore, it may be beneficial to activate telomerase, such as astragaloside IV (AST), and enhance the expression of telomeric regulatory proteins using external methods to preserve telomere integrity [ 9 ].…”

Telomere-related DNA damage response pathways in cancer therapy: prospective targets

“…The shelterin protein complex prevents chromosome ends from being recognised as DSB and activates the DDR ( Tesmer et al, 2023 ). As cells divide repeatedly and telomeres continue to shorten, shelterin binding and telomere-loop (t-loop) formation are impaired, and this weakened protection leads to telomere dysfunction, cellular senescence or apoptosis ( Shi et al, 2023 ). TRF2 overexpression has been reported to be present in a variety of malignant cancers, and its downregulation leads to cell death.…”