Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
J Cell Sci. 2022 Jul 1;135(13). doi: 10.1242/jcs.259481. Epub 2022 Jul 4.
We investigated the role of telomerase and telomere repeat-binding factor 2 (TRF2 or TERF2) in T-cell dysfunction in chronic viral infection. We found that the expression and activity of telomerase in CD4+ T (CD4T) cells from patients with hepatitis C virus (HCV) infections or people living with HIV (PLWH) were intact, but TRF2 expression was significantly inhibited at the post-transcriptional level, suggesting that TRF2 inhibition is responsible for the CD4T cell dysfunction observed during chronic viral infection. Silencing TRF2 expression in CD4T cells derived from healthy subjects induced telomeric DNA damage and CD4T cell dysfunction without affecting telomerase activity or translocation - similar to what we observed in CD4T cells from HCV patients and PLWH. These findings indicate that premature T-cell aging and dysfunction during chronic HCV or HIV infection are primarily caused by chronic immune stimulation and T-cell overactivation and/or proliferation that induce telomeric DNA damage due to TRF2 inhibition, rather than telomerase disruption. This study suggests that restoring TRF2 presents a novel approach to prevent telomeric DNA damage and premature T-cell aging, thus rejuvenating T-cell functions during chronic viral infection.
我们研究了端粒酶和端粒重复结合因子 2（TRF2 或 TERF2）在慢性病毒感染中 T 细胞功能障碍中的作用。我们发现，丙型肝炎病毒（HCV）感染或人类免疫缺陷病毒（HIV）感染者的 CD4+T（CD4T）细胞中端粒酶的表达和活性完整，但 TRF2 的表达在转录后水平受到显著抑制，这表明 TRF2 的抑制是导致慢性病毒感染期间观察到的 CD4T 细胞功能障碍的原因。沉默健康受试者来源的 CD4T 细胞中的 TRF2 表达会诱导端粒 DNA 损伤和 CD4T 细胞功能障碍，而不影响端粒酶活性或易位-类似于我们在 HCV 患者和 PLWH 的 CD4T 细胞中观察到的情况。这些发现表明，慢性 HCV 或 HIV 感染期间 T 细胞的过早衰老和功能障碍主要是由慢性免疫刺激和 T 细胞过度激活和/或增殖引起的，由于 TRF2 的抑制导致端粒 DNA 损伤，而不是端粒酶的破坏。这项研究表明，恢复 TRF2 提供了一种防止端粒 DNA 损伤和过早 T 细胞衰老的新方法，从而在慢性病毒感染期间恢复 T 细胞功能。
