APOPTOSIS INDUCED BY GAMMA-IRRADIATION, BUT NOT CD4 LIGATION, OF PERIPHERAL T-LYMPHOCYTES IN-VIVO IS P53-DEPENDENT

Mice generated by homologous recombination which carry a large deletio n of the p53 tumour suppressor gene have a high incidence of spontaneo us Thy1-positive thymic lymphoma. Extra-thymic lymphomas are rare. Apo ptosis following gamma-irradiation in thymocytes from these animals in vitro is p53-dependent and there is a marked gene dose effect: hetero zygotes show partial resistance to irradiation-induced cell death. Apo ptosis in the T-cell zones of lymph nodes following in vivo gamma-irra diation was p53-dependent, but the gene dosage effect was less marked than that noted for thymocytes. Apoptosis was induced in vivo by ligat ion of CD4 on the cell surface following intravenous injection of anti -CD4 monoclonal antibody. Apoptosis was counted in lymph node sections using a semi-automated morphometric system. This showed no evidence o f p53 dependency. In contrast to a previous report, which used a diffe rent line of p53-deficient mice, splenocytes from p53-null mice did no t differ significantly from wild-type cells,vith respect to in vitro p roliferative activity and response to mitogenic stimulation by concana valin A. This may be due to strain differences. Therefore, whilst p53 has a role in the deletion of lymphocytes which have acquired patholog ical DNA strand breaks which may lead to mutations, the results of thi s study imply that p53 is not involved in the control of apoptosis fol lowing engagement of surface receptors, nor in response to physiologic al DNA breaks and normal recombination events during T-cell ontogeny.