Frontiers in Immunology (May 2019)
Disruption of Telomere Integrity and DNA Repair Machineries by KML001 Induces T Cell Senescence, Apoptosis, and Cellular Dysfunctions
- Dechao Cao,
- Dechao Cao,
- Juan Zhao,
- Juan Zhao,
- Lam N. Nguyan,
- Lam N. Nguyan,
- Lam N. T. Nguyen,
- Lam N. T. Nguyen,
- Sushant Khanal,
- Sushant Khanal,
- Xindi Dang,
- Xindi Dang,
- Madison Schank,
- Madison Schank,
- Bal K. Chand Thakuri,
- Bal K. Chand Thakuri,
- Xiao Y. Wu,
- Xiao Y. Wu,
- Zheng D. Morrison,
- Zheng D. Morrison,
- Mohamed El Gazzar,
- Yue Zou,
- Shunbin Ning,
- Shunbin Ning,
- Ling Wang,
- Ling Wang,
- Jonathan P. Moorman,
- Jonathan P. Moorman,
- Jonathan P. Moorman,
- Zhi Q. Yao,
- Zhi Q. Yao,
- Zhi Q. Yao
Affiliations
- Dechao Cao
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Dechao Cao
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Juan Zhao
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Juan Zhao
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Lam N. Nguyan
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Lam N. Nguyan
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Lam N. T. Nguyen
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Lam N. T. Nguyen
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Sushant Khanal
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Sushant Khanal
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Xindi Dang
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Xindi Dang
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Madison Schank
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Madison Schank
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Bal K. Chand Thakuri
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Bal K. Chand Thakuri
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Xiao Y. Wu
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Xiao Y. Wu
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Zheng D. Morrison
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Zheng D. Morrison
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Mohamed El Gazzar
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Yue Zou
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Shunbin Ning
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Shunbin Ning
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Ling Wang
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Ling Wang
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Jonathan P. Moorman
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Jonathan P. Moorman
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Jonathan P. Moorman
- Department of Veterans Affairs, Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Johnson, TN, United States
- Zhi Q. Yao
- Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Zhi Q. Yao
- Division of Infectious, Inflammatory and Immunologic Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson, TN, United States
- Zhi Q. Yao
- Department of Veterans Affairs, Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Johnson, TN, United States
- DOI
- https://doi.org/10.3389/fimmu.2019.01152
- Journal volume & issue
-
Vol. 10
Abstract
T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.
Keywords
