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Published on: May 30, 2013
miR-23a-mediated TRF2 repression in CD4 T cells from PLWH
Lam N T Nguyen1, Juan Zhao1, Jaeden S Pyburn1
1Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States; Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, ETSU, Johnson City, TN, United States.
MicroRNA-23a (miR-23a) is elevated in HIV patients, suppressing TRF2 protein and accelerating CD4 T cell aging. Targeting miR-23a may restore T cell function and telomere integrity in people living with HIV.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- CD4 T cells in people living with HIV (PLWH) on antiretroviral therapy (ART) display inflammaging, characterized by inflammation, immune activation, exhaustion, senescence, and apoptosis.
- Previous studies showed that telomeric repeat factor 2 (TRF2) inhibition accelerates telomere erosion and CD4 T cell aging in PLWH.
Purpose of the Study:
- To investigate the microRNA (miRNA)-mediated mechanism inhibiting TRF2 protein in CD4 T cells of PLWH.
- To explore the potential of targeting miR-23a to restore CD4 T cell function in PLWH.
Main Methods:
- Quantification of miR-23a and TRF2 protein in CD4 T cells from PLWH and healthy subjects (HS).
- Bioinformatics analysis to identify potential miRNA targets of TRF2.
- Luciferase reporter assays to confirm miR-23a's suppression of TRF2 translation.
- T cell receptor (TCR) activation experiments.
- miR-23a mimic and knockdown studies in CD4 T cells.
Main Results:
- miR-23a was significantly increased, and TRF2 protein repressed, in CD4 T cells from PLWH compared to HS.
- Bioinformatics predicted and luciferase assays confirmed TRF2 3'UTR as a target of miR-23a, suppressing TRF2 translation.
- TCR activation increased miR-23a and decreased TRF2 expression in CD4 T cells from both PLWH and HS.
- Overexpression of miR-23a in HS CD4 T cells mimicked the PLWH phenotype (decreased TRF2, increased apoptosis).
- miR-23a knockdown in PLWH CD4 T cells increased TRF2 protein levels.
Conclusions:
- miR-23a negatively regulates TRF2 protein expression in CD4 T cells.
- Elevated miR-23a contributes to TRF2 repression and CD4 T cell aging in PLWH.
- Targeting miR-23a presents a potential therapeutic strategy to increase TRF2, protect telomere integrity, and restore CD4 T cell function in PLWH.
