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Immune Activation Induces Telomeric DNA Damage and Promotes Short-Lived Effector T Cell Differentiation in Chronic HCV Infection.
- Source :
-
Hepatology (Baltimore, Md.) [Hepatology] 2021 Nov; Vol. 74 (5), pp. 2380-2394. Date of Electronic Publication: 2021 Aug 25. - Publication Year :
- 2021
-
Abstract
- Background and Aims: Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. Although it is well known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation-induced T cell dysfunctions during HCV infection remain elusive.<br />Approach and Results: Here, we demonstrated that circulating CD4 <superscript>+</superscript> T cells from patients who are chronically HCV-infected exhibit an immune activation status, as evidenced by the overexpression of cell activation markers human leukocyte antigen-antigen D-related, glucose transporter 1, granzyme B, and the short-lived effector marker CD127 <superscript>-</superscript> killer cell lectin-like receptor G1 <superscript>+</superscript> . In contrast, the expression of stem cell-like transcription factor T cell factor 1 and telomeric repeat-binding factor 2 (TRF2) are significantly reduced in CD4 <superscript>+</superscript> T cells from patients who are chronically HCV-infected compared with healthy participants (HP). Mechanistic studies revealed that CD4 <superscript>+</superscript> T cells from participants with HCV exhibit phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling hyperactivation on T cell receptor stimulation, promoting proinflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HP T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in CD4 T cells prevented telomeric DNA damage.<br />Conclusions: These results suggest that modulation of immune activation through inhibiting Akt signaling and protecting telomeres through enhancing TRF2 expression may open therapeutic strategies to fine tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.<br /> (© 2021 by the American Association for the Study of Liver Diseases.)
- Subjects :
- Adult
Aged
Apoptosis genetics
Apoptosis immunology
Cells, Cultured
DNA Damage genetics
Female
Gene Knockdown Techniques methods
Hepatitis C, Chronic virology
Humans
Lymphocyte Activation
Male
Middle Aged
Persistent Infection genetics
Persistent Infection immunology
Persistent Infection virology
Phosphatidylinositol 3-Kinases metabolism
Proto-Oncogene Proteins c-akt metabolism
RNA, Viral genetics
Signal Transduction genetics
Signal Transduction immunology
TOR Serine-Threonine Kinases metabolism
Telomeric Repeat Binding Protein 2 genetics
Telomeric Repeat Binding Protein 2 metabolism
Transduction, Genetic methods
Young Adult
CD4-Positive T-Lymphocytes immunology
Cell Differentiation immunology
DNA Damage immunology
Hepacivirus genetics
Hepatitis C, Chronic genetics
Hepatitis C, Chronic immunology
Telomere genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1527-3350
- Volume :
- 74
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Hepatology (Baltimore, Md.)
- Publication Type :
- Academic Journal
- Accession number :
- 34110660
- Full Text :
- https://doi.org/10.1002/hep.32008