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. 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 CD3 gamma-deficient mice completely reverses the cell survival defect in CD3 gamma-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.
Haks
M C
MC
Division of Immunology, The Netherlands Cancer Institute, Amsterdam.
Krimpenfort
P
P
van den Brakel
J H
JH
Kruisbeek
A M
AM
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000166:cytology / Q000473:pathology; D019076:Transgenes / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics
D017252:CD3 Complex; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53