REGULATION OF IMMUNE RESPONSES BY APOPTOTIC CELLS

Billions of cells die everyday as a result of normal tissue turnover, infection, trauma or injury. These dead cells are taken up, processed and presented to T cells by antigen presenting cells resulting in tolerance or immunity. Apoptotic cells induce tolerance; however, the precise mechanisms are still unknown. Previous studies have shown that direct infusion of apoptotic cells induce tolerance mediated by TRAIL-expressing CD8+ T cells. We hypothesized that immunologic tolerance induced by apoptotic cells is dependent on the activation status of apoptotic cells and mediated by direct killing of target cells by TRAIL-expressing CD8+ T cells. Three different experimental systems were used to elucidate the mechanisms by which apoptotic cells regulate immune responses. Using a classical system of tolerance induction, we examined the immunological consequence of intravenous (i.v.) delivery of ex vivo-generated naïve or activated apoptotic cells. Naïve apoptotic cells induced tolerance when injected i.v.; however, previously activated apoptotic cells induced immunity. Further analysis revealed a ke