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Stadanlick JE, Zhang ZQ, Lee SY, Hemann M, Biery M, Carleton MO, Zambetti GP, Anderson SJ, Oravecz T, Wiest DL
Developmental Arrest of T Cells in Rpl22-Deficient Mice Is Dependent upon Multiple p53 Effectors
Journal of Immunology (2011) 187:664-675.
alpha beta and gamma delta lineage T cells are thought to arise from a common CD4(-)CD8-progenitor in the thymus. However, the molecular pathways controlling fate selection and maturation of these two lineages remain poorly understood. We demonstrated recently that a ubiquitously expressed ribosomal protein, Rpl22, is selectively required for the development of alpha beta lineage T cells. Germline ablation of Rpl22 impairs development of alpha beta lineage, but not gamma delta lineage, T cells through activation of a p53-dependent checkpoint. In this study, we investigate the downstream effectors used by p53 to impair T cell development. We found that many p53 targets were induced in Rpl22(-/)-thymocytes, including miR-34a, PUMA, p21(waf), Bax, and Noxa. Notably, the proapoptotic factor Bim, while not a direct p53 target, was also strongly induced in Rpl22(-/-) T cells. Gain-of-function analysis indicated that overexpression of miR-34a caused a developmental arrest reminiscent of that induced by p53 in Rpl22-deficient T cells; however, only a few p53 targets alleviated developmental arrest when individually ablated by gene targeting or knockdown. Co-elimination of PUMA and Bim resulted in a nearly complete restoration of development of Rpl22(-/-) thymocytes, indicating that p53-mediated arrest is enforced principally through effects on cell survival. Surprisingly, co-elimination of the primary p53 regulators of cell cycle arrest (p21(waf)) and apoptosis (PUMA) actually abrogated the partial rescue caused by loss of PUMA alone, suggesting that the G1 checkpoint protein p21(waf) facilitates thymocyte development in some contexts. The Journal of Immunology, 2011, 187: 664-675.
Publication Date: 2011-07-01.
PMCID: PMC3131471
Last updated on Monday, May 04, 2020