The identification of a novel T cell activation state controlled by a diabetogenic gene

The cyclin-dependent kinase inhibitor p27(kip) regulates the cell cycle at the G(1)-S phase restriction point. S phase entry and cell cycle commitment in peripheral T cells requires p27(kip) degradation, normally initiated by the receipt of costimulatory signals such as those provided by B7.1 or IL- 2. We have previously reported that T cells from BioBreeding (BB)-diabetes- prone (DP) rats exhibit decreased costimulatory requirements for activation and cell cycle entry. In the present study, we find that peripheral T cell subsets from BB-DP rats demonstrate activation-like characteristics, inclu ding significantly reduced levels of p27(kip) as well as increased levels o f proliferating cell nuclear Ag (PCNA), Since our previous studies have est ablished that expression of extracellular activation markers are relatively low in unmanipulated peripheral BB-DP T cells; this p27(low) PCNA(high) ph enotype represents a novel activation state, Analyses of T cell subsets fro m congenic rats demonstrate that this phenotype segregates with the lyp dia betogenic locus and that the p27(low) pCNA(high) phenotype is T cell specif ic. This p27(low) PCNA(high) phenotype is not seen in medullary thymocytes, but appears abruptly in the recent thymic emigrant population, suggesting that the lyp locus does not act directly on cell cycle regulators but rathe r alters the interaction between T cells and the peripheral environment, Th ese results provide a biochemical basis for costimulation-independent activ ation and suggest a mechanism whereby a diabetes susceptibility gene contri butes to disease development.