CDK4 expression and activity are required for cytokine responsiveness in T cells.
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 approximately 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.
Modiano
J F
JF
Center for Cancer Causation and Prevention, AMC Cancer Research Center, Denver, CO 80214, USA. modianoj@amc.org
Mayor
J
J
Ball
C
C
Fuentes
M K
MK
Linthicum
D S
DS
D002460:Cell Line; D002478:Cells, Cultured; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007121:Immunocompetence / Q000235:genetics; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases