BET Bromodomain Inhibition Suppresses Human T Cell Function
| Autor: | Elaine M. Pinheiro, Madhavi L. Bandi, Manjiri Sathe, Peter Georgiev, Yun Wang, Eric S. Muise, Stuart D. Shumway, Wendy M. Blumenschein |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
CD4-Positive T-Lymphocytes
medicine.medical_treatment T cell Immunology Gene Expression Apoptosis CD8-Positive T-Lymphocytes Lymphocyte Activation Immune system medicine Humans Immunology and Allergy Cell Proliferation Cyclin Effector Chemistry Proteins General Medicine G1 Phase Cell Cycle Checkpoints Healthy Volunteers Bromodomain Cell biology medicine.anatomical_structure Cytokine Cytokines Acetanilides Glycolysis Heterocyclic Compounds 3-Ring G1 phase Memory T cell Immunosuppressive Agents Signal Transduction |
| Zdroj: | ImmunoHorizons. 3:294-305 |
| ISSN: | 2573-7732 |
| Popis: | Bromodomain and extraterminal domain (BET) proteins help direct the differentiation of helper T cell subsets, but their role in activated T cell function has not been described in detail. In this study, we investigate various consequences of epigenetic perturbation in human T lymphocytes using MK-8628, a potent and highly selective inhibitor of BET proteins. MK-8628 reduces the expression of canonical transcripts directing the proliferation, activation, and effector function of T lymphocytes. Treatment with MK-8628 abolishes the expression of key cyclins required for cell cycle progression and induces G1 cell cycle arrest in TCR-activated lymphocytes. This antiproliferative phenotype partially results from T lymphocyte apoptosis, which is exacerbated by MK-8628. In naive and memory T cell subsets, MK-8628 antagonizes T cell activation and suppresses polyfunctional cytokine production. Collectively, our results describe potent immunosuppressive effects of BET inhibition on human T cell biology. These results have important implications for immune modulatory targeting of BET proteins in the settings of T cell–driven autoimmune inflammation. |
| Databáze: | OpenAIRE |
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