ANTIGEN-INDUCED APOPTOSIS (PROPRIOCIDAL REGULATION) OF MATURE T LYMPHOCYTES

这个项目是基于我们的发现，刺激抗原

This project is based on our discovery that stimulation of the antigen receptor of mature T cells following exposure of the cells to mitogenic lymphokines such as IL-2 leads to the induction of programmed cell death or apoptosis (propriocidal regulation). We are interested in the mechanism of propriocidal regulation. We are also studying whether this mechanism can explain certain phenomenon of immunological "suppression" that have been previously studied and how this mechanism plays a role in various immunomodulatory strategies being attempted for human disease. We have studied the parameters that control apoptosis during high dose suppression. We found that suppression correlates with IL-2 receptor expression and increased proliferation and was a function of the efficiency of antigen presentation. We have also demonstrated that T cell blasts derived from mice containing a germline deficiency of the p53 tumor suppressor gene are susceptible to TCR-induced apoptosis to the same degree as wild type derived T cells. By contrast, p53-/-T lymphocyte blasts are protected from death caused by the topoisomerase II inhibitors etoposide and teniposide. We also analyzed the expression of Bax and p21 which are induced by p53 in many cell-types and play a role in apoptosis. We found that bax and p21 mRNAs are upregulated in a p53-dependent manner in T cell blasts following stimulation with anti- CD3epsilon mAb or treatment with the topoisomerase inhibitors. This indicates that the p53-pathway is upregulated when proliferating T cells are stimulated through the T cell receptor, but T cell apoptosis can occur via a p53 independent pathway. Currently, we are exploring the role of propriocidal apoptosis in tolerance induced by antigen given by different routes including intravenous or intraperitoneal injection or oral administration. Oral tolerance has been proposed as a means to combat various autoimmune diseases by the stimulation of specialized suppressor cells. We are studying whether oral tolerance effects immune responsiveness by causing T cell apoptosis by the propriocidal mechanism. Finally, in AIDS we have been studying the various types of T cell death that occur. We are testing the hypothesis that the loss of selected populations of CD8 T cells that are vital for killing infected CD4 cells may occur by the propriocidal mechanism. Such an event could debilitate the immune response against HIV and lead to progression of disease in AIDS.