Shelterin dysfunction promotes CD4⁺ T cell senescence in Beh?et's disease

Objectives: To investigate the potential role of shelterin dysfunction in na & iuml;ve CD4(+) T cells in the pathogenesis of Beh & ccedil;et's disease (BD).Methods: Na & iuml;ve 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) were evaluated. Telomere repeat factor-2 (TRF2) silencing was conducted for further validation.Results: Compared with HC, BD patients had significantly decreased na & iuml;ve CD4(+) T cells, increased cell apoptosis, senescence, and productions of TNF-alpha and IFN-gamma upon activation. Notably, BD na & iuml;ve CD4(+) T cells had shortened telomere, impaired telomerase activity, and expressed lower levels of shelterin subunits TRF2, TRF1- and TRF2-Interacting Nuclear Protein 2 (TIN2) and Repressor/Activator Protein 1 (RAP1). Furthermore, BD na & iuml;ve CD4(+) T cells exhibited significantly increased DDR, evidenced by elevated phosphorylated ataxia telangiectasia (AT) mutated (pATM), phosphorylated p53 (pp53) and p21. Finally, TRF2 silencing markedly upregulated DDR, apoptosis and proinflammatory cytokines production in HC na & iuml;ve CD4(+) T cells.Conclusion: Our study demonstrated that TRF2 deficiency in BD na & iuml;ve CD4(+) T cells promoted cell apoptosis and senescence, leading to proinflammatory cytokines overproduction. Therefore, restoring TRF2 might be a promising therapeutic strategy for BD.