CDK4 expression and activity are required for cytokine responsiveness in T cells
| Autor: | Jocelyne Mayor, Jaime F. Modiano, M K Fuentes, Carrie Ball, Darwin S. Linthicum |
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| Předmět: |
Interleukin 2
T-Lymphocytes T cell Immunology Biology Lymphocyte Activation Jurkat cells Cell Line Interleukin 21 Proto-Oncogene Proteins Immune Tolerance medicine Humans Immunology and Allergy Cytotoxic T cell RNA Messenger IL-2 receptor Cells Cultured Interleukin 3 ZAP70 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinases Cell biology Enzyme Activation medicine.anatomical_structure Cytokines Interleukin-2 Immunocompetence medicine.drug |
| Zdroj: | Scopus-Elsevier |
| Popis: | Stimulation of lymphocytes through the Ag receptor can lead to cytokine responsiveness or unresponsiveness. We examined the importance of cyclin-dependent kinase (CDK)4 to establish and maintain IL-2 responsiveness in human T cells. Our results show that a herbimycin A- and staurosporine-sensitive phase of CDK4 expression and activity preceded the acquisition of IL-2-responsiveness in mitogen-stimulated peripheral blood T cells. Intriguingly, CDK4 expression and activity were demonstrable in purified unstimulated peripheral blood T cells from ∼30% (5/16) of healthy individuals examined for this study. These T cells proliferated in response to IL-2 without additional mitogens, and both the expression and activity of CDK4 and the ability to respond to cytokines were resistant to herbimycin A and staurosporine. The pattern of CDK4 expression and response to IL-2 in this subset of individuals resembled that seen in the human IL-2-dependent Kit-225 T cell line. However, in contrast to normal T cells, Kit-225 cells were rendered unresponsive to IL-2 by stimulation through the Ag receptor. In these cells, PHA, anti-CD3, or PMA induced marked reductions of CDK4 expression and activity that paralleled IL-2 unresponsiveness, and these effects were not reversible by IL-2. Furthermore, IL-2-dependent proliferation could be similarly inhibited in Kit-225 cells by overexpression of the CDK inhibitors p16/Ink4-a or p21/Waf-1a or by overexpression of a kinase-inactive CDK4 mutant. The data indicate that CDK4 expression and activity are necessary to induce and maintain cytokine responsiveness in T cells, suggesting that CDK4 is important to link T cell signaling pathways to the machinery that controls cell cycle progression. |
| Databáze: | OpenAIRE |
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