p53 prevents maturation to the CD4+CD8+ stage of thymocyte differentiation in the absence of T cell receptor rearrangement.
Rearrangement of the immunoglobulin (Ig) and T cell receptor (TCR) gene loci allows for the generation of B and T lymphocytes with antigen-specific receptors. Complete rearrangement and expression of the TCR-beta chain enables immature thymocytes to differentiate from the CD4-CD8- to the CD4+CD8+ stage mice in which rearrangement is impaired, such as severe combined immunodeficient (SCID) mice or recombinase activating gene-deficient (RAG-/-) mice, lack mature B and T lymphocytes. Thymocytes from these mice are arrested at the CD4-CD8- stage of T cell development. We previously observed that thymocytes from RAG-2-/- mice exposed to gamma radiation differentiate from CD4-CD8- into CD4+CD8+ without TCR-beta chain rearrangement. We now report that irradiated RAG-2-/- thymocytes undergo direct somatic mutations at the p53 gene locus, and that p53 inactivation is associated with maturation of RAG2-/- thymocytes to the CD4+CD8+ stage. Generation of RAG2-/- and p53-/- double-deficient mice revealed that, in the absence of TCR-beta chain rearrangement, loss of p53 function is sufficient for CD4-CD8- thymocytes to differentiate into the CD4+CD8+ stage of T cell development. Our data provide evidence for a novel p53 mediated checkpoint in early thymocyte development that regulates the transition of CD4-CD8- into CD4+CD8+ thymocytes.
Jiang
D
D
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA.
Lenardo
M J
MJ
Zúñiga-Pflücker
J C
JC
D000818:Animals; D002772:Cholera Toxin / Q000276:immunology; D007082:Ileum / Q000166:cytology / Q000276:immunology; D007070:Immunoglobulin A / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology*; D007583:Jejunum / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology; D014611:Vaccination
D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013745:Tetanus Toxoid; D002772:Cholera Toxin