DIFFERENTIAL REQUIREMENTS FOR INTERLEUKIN-2 DISTINGUISH THE EXPRESSION AND ACTIVITY OF THE CYCLIN-DEPENDENT KINASES CDK4 AND CDK2 IN HUMAN T-CELLS

We examined the expression and activity of Cdk4 and Cdk2 in resting, c ompetent, and proliferating normal human T cells, Expression of Cdk4 b ut not of Cdk2 was induced in competent T cells independent of an IL-2 signal, This up-regulation of Cdk4 mRNA and protein was resistant to the immunosuppressant drugs cyclosporin A (CsA) and FK506, A further i ncrease in Cdk4 expression was seen upon stimulation of competent T ce lls by IL 2, as was de novo expression of Cdk2. Cyclin D2, a Cdk4 part ner, showed similar patterns of regulation as Cdk4, The increases in C dk4 and cyclin D2 expression seen in competent T cells were functional ly significant since Cdk4 immunoprecipitates from these cells phosphor ylated recombinant RE protein in vitro, Despite the lack of an increas e in the expression of Cdk2, a small pool of pre-existing Cdk2 protein detected in resting T cells could be activated upon induction of comp etence, These data demonstrate that 1) the signals that lead to induct ion of competence in T cells stimulate an IL-Q-independent and CsA res istant phase of Cdk4 and cyclin D2 expression, Cdk4 kinase activity, a nd Cdk2 kinase activity, and 2) IL-2 stimulates a second phase of Cdk4 and cyclin D2 expression and de novo expression of Cdk2 in these cell s, The data show that the expression and activity of these major cell cycle regulatory proteins are controlled differentially by growth fact ors and indicate a role for Cdk4 and cyclin D2 in T cell cycle entry a nd/or early G(1) progression and for Cdk2 in later G(1) progression an d G(1)/S transition.