Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction
| Autor: | Michael L. Freeman, Carey L Shive, Soumya Panigrahi, Souheil-Antoine Younes, Konstantin V. Shmagel, Scott F. Sieg, Benigno Rodriguez, Aarthi Talla, Susan Pereira Ribeiro, Larisa B. Korolevskaya, Donald D. Anthony, Leonard H. Calabrese, Robert Balderas, Evgeniya V. Saidakova, Mark J. Cameron, Daniel C. Douek, Michael M. Lederman, Pushpa Pandiyan, Sophia Alison Zweig, Leonid Margolis |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine T cell HIV Infections Mitochondrion Biology T-Lymphocytes Regulatory Flow cytometry Mitochondrial Proteins 03 medical and health sciences 0302 clinical medicine Immune system medicine Humans Interleukin-15 medicine.diagnostic_test General Medicine Middle Aged Cell cycle TFAM Acquired immune system Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha CD4 Lymphocyte Count Mitochondria DNA-Binding Proteins 030104 developmental biology medicine.anatomical_structure Anti-Retroviral Agents Mitochondrial biogenesis 030220 oncology & carcinogenesis Immunology HIV-1 Female Research Article Transcription Factors |
| Zdroj: | Journal of Clinical Investigation. 128:5083-5094 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci120245 |
| Popis: | Immune nonresponder (INR) HIV-1-infected subjects are characterized by their inability to reconstitute the CD4+ T cell pool after antiretroviral therapy. This is linked to poor clinical outcome. Mechanisms underlying immune reconstitution failure are poorly understood, although, counterintuitively, INRs often have increased frequencies of circulating CD4+ T cells in the cell cycle. While cycling CD4+ T cells from healthy controls and HIV+ patients with restored CD4+ T cell numbers complete cell division in vitro, cycling CD4+ T cells from INRs do not. Here, we show that cells with the phenotype and transcriptional profile of Tregs were enriched among cycling cells in health and in HIV infection. Yet there were diminished frequencies and numbers of Tregs among cycling CD4+ T cells in INRs, and cycling CD4+ T cells from INR subjects displayed transcriptional profiles associated with the impaired development and maintenance of functional Tregs. Flow cytometric assessment of TGF-β activity confirmed the dysfunction of Tregs in INR subjects. Transcriptional profiling and flow cytometry revealed diminished mitochondrial fitness in Tregs among INRs, and cycling Tregs from INRs had low expression of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) and transcription factor A for mitochondria (TFAM). In vitro exposure to IL-15 allowed cells to complete division, restored the expression of PGC1α and TFAM, and regenerated mitochondrial fitness in the cycling Tregs of INRs. Our data suggest that rescuing mitochondrial function could correct the immune dysfunction characteristic of Tregs in HIV-1-infected subjects who fail to restore CD4+ T cells during antiretroviral therapy. |
| Databáze: | OpenAIRE |
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