Pre-TCR signaling and inactivation of p53 induces crucial cell survival pathways in pre-T cells

Signaling through the pre-TCR is essential for early T cell development and is severely impaired in mice lacking the CD3 gamma chain of the pre-TCR. W e here address the molecular mechanisms underlying this defect. Impaired pr e-TCR signaling is shown to be associated with a profound increase in the n umber of apoptotic CD4(-)CD8(-) (DN) thymocytes. introduction of p53 defici ency into CD3 gamma-deficient mice completely reverses the cell survival de fect in CD3 gamma-deficient DN thymocytes and rescues the block in pre-T ce ll differentiation. In addition, the CD4(+)CD8(+) (DP) compartment is expan ded to its normal size. These findings suggest that the pre-TCR regulates p rogression through the DNA-damage checkpoint of the DN to DP transition by inactivating p53.