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 deletion of the p53 tumour suppressor gene have a high incidence of spontaneous Thy1-positive thymic lymphoma. Extra-thymic lymphomas are rare. Apoptosis following gamma-irradiation in thymocytes from these animals in vitro is p53-dependent and there is a marked gene dose effect: heterozygotes show partial resistance to irradiation-induced cell death. Apoptosis in the T-cell zones of lymph nodes following in vivo gamma-irradiation was p53-dependent, but the gene dosage effect was less marked than that noted for thymocytes. Apoptosis was induced in vivo by ligation 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 of p53 dependency. In contrast to a previous report, which used a different line of p53-deficient mice, splenocytes from p53-null mice did not differ significantly from wild-type cells with respect to in vitro proliferative activity and response to mitogenic stimulation by concanavalin A. This may be due to strain differences. Therefore, whilst p53 has a role in the deletion of lymphocytes which have acquired pathological DNA strand breaks which may lead to mutations, the results of this study imply that p53 is not involved in the control of apoptosis following engagement of surface receptors, nor in response to physiological DNA breaks and normal recombination events during T-cell ontogeny.
Malcomson
R D
RD
Department of Pathology, University Medical School, Edinburgh, U.K.
Clarke
A R
AR
Peter
A
A
Coutts
S B
SB
Howie
S E
SE
Harrison
D J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D015704:CD4 Antigens / Q000276:immunology*; D018929:Cell Culture Techniques; D003208:Concanavalin A / Q000276:immunology; D005720:Gamma Rays; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016159:Tumor Suppressor Protein p53; D003208:Concanavalin A