The development of diabetes spontaneously in the BB rat requires a diabetogenic gene termed lyp. Lyp is named after the phenotype it creates, peripheral T cell lymphopenia. Most T cells from lymphopenic animals have a dramatically shortened life span and when they fail to become members of the long lived peripheral T cell pool the lymphopenic environment is created. A major focus of our work has been directed to understanding how the lyp gene and the resultant lymphopenia contribute to disease. Our recent observations indicate that most T cells from diabetes-prone BB animals express a novel activation state, defined by a quiescent cell surface but activated internal measures of cell cycle machinery. We believe this novel activation state is the impetus through which autoreactive T cells become activated. In this application we will test several hypotheses formulated from our data. First, the cause of the lymphopenia is the lyp gene mediated cell cycle arrest of T cells as they attempt to progress from G1 to S phase. Second, lymphopenia creates space in the periphery. Space provides clonal expansion signals for recent thymic emigrants that bear T cell receptors for self antigens. Third, autoreactive T cells can overcome the lyp gene mediated cell cycle arrest because they express high affinity receptors for self antigens. If our hypotheses are correct, as tested in the experiments proposed in this application, the data generated will permit us to understand how at least one genetic susceptibility region contributes to disease in this rat model.
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