CDK4 expression and activity are required for cytokine responsiveness in Tcells

Stimulation of lymphocytes through the Ag receptor can lead to cytokine res ponsiveness or unresponsiveness. We examined the Importance of cyclin depen dent kinase (CDK)4 to establish and maintain IL-2 responsiveness in human T cells. Our results show that a herbimycin A- and staurosporine-sensitive p hase of CDK4 expression and activity preceded the acquisition of IL-2-respo nsiveness in mitogen-stimulated peripheral blood T cells. Intriguingly, CDK 4 expression and activity were demonstrable in purified unstimulated periph eral blood T cells from similar to 30% (5/16) of healthy individuals examin ed for this study. These T cells proliferated in response to IL-2 without a dditional mitogens, and both the expression and activity of CDK4 and the ab ility to respond to cytokines were resistant to herbimycin A and staurospor ine, 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 u nresponsive to IL-2 by stimulation through the Bg receptor, In these cells, PHA, anti-CDS, or PMA induced marked reductions of CDK4 expression and act ivity that paralleled IL-2 unresponsiveness, and these effects were not rev ersible by IL-2, Furthermore, IL-2-dependent proliferation could be similar ly inhibited in Kit-225 cells by overexpression of the CDK inhibitors p16/I nk4-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 i mportant to link T cell signaling pathways to the machinery that controls c ell cycle progression.