p53−/− mice are more susceptible than WT mice to low dose streptozotocin-induced diabetes, a condition that
requires lymphocytes for induction of the disease 9 and destruction of islets. T-cell dependent collagen- and methylated BSA-induced arthritis, but not passive Ab-induced selleck compound arthritis, was more severe in p53−/− mice than in WT counterparts 10, 11. Increased expression of p53 in brain parenchymal T cells of rats with EAE has been reported and this expression was highest at the peak of the disease and declined thereafter, suggesting a role for p53 in pathogenesis of EAE 12. In accordance, p53−/− mice developed more severe EAE than WT mice following immunization with myelin oligodendrocyte glycoprotein peptide 35–55 13. These studies indicate a possible role of p53 in suppressing T-cell responses in vivo. However, a detailed mechanistic study regarding the role of p53 in regulating T cells responses is poorly defined. By analogy to the well-known tumor suppressor functions, p53 may mediate cell cycle and/or apoptosis signals that limit T-cell responses. In vitro studies have AZD2014 solubility dmso shown that activation-induced cell death (AICD) is comparable
in preactivated WT and p53−/− T cells 14, 15. Therefore, it is surprising that 70–90% of p53−/− mice preferentially develop lymphomas, most of which are thymic lymphomas 16, 17, suggesting a pivotal role for p53 in regulating T-cell apoptosis in vivo under normal physiological conditions. Although gamma radiation-induced apoptosis of thymocytes is dependent on p53 18, 19, it is very difficult to believe that under normal housing conditions, p53−/− mice are being exposed to a dose of ionizing/gamma radiation that would otherwise cause apoptosis of WT T cells. The major role of p53 is to induce cell cycle arrest in response to DNA breaks, allowing DNA repair to take place
and thus correct mutations in DNA. Therefore, it is anticipated that DNA breaks may lead to oncogenic mutation and development of lymphomas in p53−/− CYTH4 mice. RAG product-mediated cleavage of specific DNA sequences is required for assembly of TCR genes. The rarity of clonal chromosomal translocations involving TCR loci in lymphomas of p53−/− mice and development of T-cell lymphomas in p53−/−RAG1−/− and p53−/−RAG2−/− mice suggest that RAG-mediated DNA breaks are not required for development of T-cell lymphomas in the absence of p53 20. If RAG-mediated programmed DNA breaks are not required for development of lymphomas in p53−/− mice, what is the stimulus for spontaneous development of lymphomas in p53−/− mice? Alternatively, double stranded DNA breaks that arise in S-phase through DNA replication errors during physiological expansion of immature and mature T cells during their development, maintenance and/or immune responses could contribute toward oncogenic mutations and development of lymphomas in p53−/− mice.