Pre-TCR Signaling and Inactivation of p53 Induces Crucial Cell Survival Pathways in Pre-T Cells

Abstract

Signaling through the pre-TCR is essential for early T cell development and is severely impaired in mice lacking the CD3γ chain of the pre-TCR. We here address the molecular mechanisms underlying this defect. Impaired pre-TCR signaling is shown to be associated with a profound increase in the number of apoptotic CD4 −CD8 − (DN) thymocytes. Introduction of p53 deficiency into CD3γ-deficient mice completely reverses the cell survival defect in CD3γ-deficient DN thymocytes and rescues the block in pre-T cell differentiation. In addition, the CD4 +CD8 + (DP) compartment is expanded to its normal size. These findings suggest that the pre-TCR regulates progression through the DNA-damage checkpoint of the DN to DP transition by inactivating p53.