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The Identification of a Novel T Cell Activation State Controlled by a Diabetogenic Gene¹

Jodene K. Moore^*, Robert I. Scheinman and Donald Bellgrau^2,*

^* Department of Immunology, Barbara Davis Center for Childhood Diabetes, School of Medicine and Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262

The cyclin-dependent kinase inhibitor p27^kip regulates the cell cycle at the G₁-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, including significantly reduced levels of p27^kip as well as increased levels of proliferating cell nuclear Ag (PCNA). Since our previous studies have established that expression of extracellular activation markers are relatively low in unmanipulated peripheral BB-DP T cells; this p27^low PCNA^high phenotype represents a novel activation state. Analyses of T cell subsets from congenic rats demonstrate that this phenotype segregates with the lyp diabetogenic locus and that the p27^low PCNA^high phenotype is T cell specific. 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 rather alters the interaction between T cells and the peripheral environment. These results provide a biochemical basis for costimulation-independent activation and suggest a mechanism whereby a diabetes susceptibility gene contributes to disease development.

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