TCR engagement in the absence of cell cycle progression leads to T cell anergy independent of p27^Kip1

We have proposed a model in which the prevention of anergy by costimulation is the result of IL-2-induced G1 to S phase cell cycle progression. Here we demonstrate that the reversal of anergy by exogenous IL-2 also occurs during this window of the cell cycle. Recently, it has been proposed that the cell cycle inhibitor p27^Kip1 is an anergic factor. In contrast, our data demonstrate that during the induction, maintenance and rechallenge phases of anergy, p27^Kip1 levels do not correlate with the anergic phenotype. Although p27^Kip1 levels were down-regulated by IL-2 during the G1 to S phase transition, the amount of IL-2 required to produce this effect was far lower than that required to prevent the induction of anergy. Furthermore, T cell lines from p27^Kip1 knockout mice were anergized as well as T cells from mice that were heterozygous for p27^Kip1. Interestingly, the forced overexpression of p27^Kip1 was able to decrease IL-2 promoter-induced transcription, suggesting that the cell cycle machinery may be involved in T cell activation; however, physiological levels of p27^Kip1 did not prevent IL-2 transcription. Overall, our data serve to disassociate the ability of IL-2 to down-regulate p27^Kip1 and its ability to prevent or reverse anergy.