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.