TCR engagement in the absence of cell cycle progression leads to T cell anergy independent of p27Kip1

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Abstract
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 p27Kip1 is an anergic factor. In contrast, our data demonstrate that during the induction, maintenance and rechallenge phases of anergy, p27Kip1 levels do not correlate with the anergic phenotype. Although p27Kip1 levels were down-regulatedby 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 p27Kip1 knockout mice were anergized as well as T cells from mice that were heterozygous for p27Kip1. Interestingly, the forced overexpression of p27Kip1 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 p27Kip1 did not prevent IL-2 transcription. Overall, our data serve to disassociate the ability of IL-2 to down-regulate p27Kip1 and its ability to prevent or reverse anergy.

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