TRF2 inhibition rather than telomerase disruption drives CD4T cell dysfunction during chronic viral infection
© 2022. Published by The Company of Biologists Ltd..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:135 |
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| Enthalten in: |
Journal of cell science - 135(2022), 13 vom: 01. Juli |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nguyen, Lam Ngoc Thao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.07.2022 Date Revised 05.07.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1242/jcs.259481 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Nguyen, Lam Ngoc Thao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a TRF2 inhibition rather than telomerase disruption drives CD4T cell dysfunction during chronic viral infection |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. Published by The Company of Biologists Ltd. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a HCV | |
| 650 | 4 | |a HIV | |
| 650 | 4 | |a T-cell dysfunction | |
| 650 | 4 | |a TRF2 | |
| 650 | 4 | |a Telomerase | |
| 650 | 4 | |a Telomere erosion | |
| 650 | 7 | |a TERF2 protein, human |2 NLM | |
| 650 | 7 | |a Telomeric Repeat Binding Protein 2 |2 NLM | |
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| 700 | 1 | |a Nguyen, Lam Nhat |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Schank, Madison |e verfasserin |4 aut | |
| 700 | 1 | |a Dang, Xindi |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Dechao |e verfasserin |4 aut | |
| 700 | 1 | |a Khanal, Sushant |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiao Y |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jinyu |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Shunbin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a El Gazzar, Mohamed |e verfasserin |4 aut | |
| 700 | 1 | |a Moorman, Jonathan P |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Zhi Q |e verfasserin |4 aut | |
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