A role for E2F1 in the induction of apoptosis during thymic negative selection

Thymic negative selection is the process in which maturing thymocytes that express T-cell receptors recognizing self are eliminated by apoptotic cell death. The molecular mechanism by which this occurs is poorly understood. N otably, genes involved in cell death, even thymocyte death, such as Fas, Fa s-ligand, p53, caspase-1, caspase-3, and caspase-9 and Bcl-2 have been foun d to not be required for normal thymic negative selection. We have demonstr ated previously that E2F1-deficient mice have a defect in thymocyte apoptos is, Here we show that E2F1 is required for normal thymic negative selection . Furthermore, we observed an E2F1-dependent increase of p53 protein levels during the process of thymic clonal deletion, which suggests that E2F1 reg ulates activation-induced apoptosis of self-reactive thymocytes by a p53-de pendent mechanism, In contrast, other apoptotic pathways operating on devel oping thymocytes, such as glucocorticoid-induced cell death, are not mediat ed by E2F1. The T lymphocytes that escape thymic negative selection migrate to the peripheral immune system but do not appear to be autoreactive, indi cating that there may exist E2F1-independent mechanisms of peripheral toler ance, which protect mice from developing an autoimmune response. We expect that E2F1-deficient mice will provide a useful tool for understanding the m olecular mechanism of and the immunological importance of thymic negative s election.