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*
Center for Cancer Causation and Prevention, AMC Cancer Research Center, Denver, CO 80214; and
Department of Pathobiology, Texas A&M University, College Station, TX 77843
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.
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