Jiang D, Lenardo M J, Zúñiga-Pflücker J C
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA.
J Exp Med. 1996 Apr 1;183(4):1923-8. doi: 10.1084/jem.183.4.1923.
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.
免疫球蛋白(Ig)和T细胞受体(TCR)基因座的重排使得能够产生具有抗原特异性受体的B和T淋巴细胞。TCR-β链的完全重排和表达能使未成熟胸腺细胞从CD4-CD8-阶段分化为CD4+CD8+阶段。在重排受损的小鼠中,如严重联合免疫缺陷(SCID)小鼠或重组酶激活基因缺陷(RAG-/-)小鼠,缺乏成熟的B和T淋巴细胞。这些小鼠的胸腺细胞停滞在T细胞发育的CD4-CD8-阶段。我们之前观察到,暴露于γ辐射的RAG-2-/-小鼠的胸腺细胞在没有TCR-β链重排的情况下从CD4-CD8-分化为CD4+CD8+。我们现在报告,受辐射的RAG-2-/-胸腺细胞在p53基因座发生直接体细胞突变,并且p53失活与RAG2-/-胸腺细胞成熟到CD4+CD8+阶段相关。RAG2-/-和p53-/-双缺陷小鼠的产生表明,在没有TCR-β链重排的情况下,p53功能丧失足以使CD4-CD8-胸腺细胞分化为T细胞发育的CD4+CD8+阶段。我们的数据为早期胸腺细胞发育中一种新的p53介导的检查点提供了证据,该检查点调节CD4-CD8-胸腺细胞向CD4+CD8+胸腺细胞的转变。