Radiation-induced apoptosis is differentially regulated in primary B cells from normal mice and mice with the CBA/N X-linked immunodeficiency.
Normal B cells responsive to thymus independent-type 1 Ags (TI-1) are resistant to low doses of ionizing radiation in vivo (200-300 cGy), compared with TI-1 responsive B cells of mice with the CBA/N X-linked immunodeficiency (xid). This difference in radiosensitivity is an intrinsic B cell property; normal B cells adoptively transferred into xid mice remain TI-1-responsive after irradiation in situ. Because irradiation induces programmed cell death (PCD) in lymphocytes, we determined whether PCD were regulated differently in normal and xid B cells. B cells isolated immediately after irradiation from normal or xid donors when cultured without stimulators became apoptotic with the same kinetics and to the same extent, showing that apoptosis was induced equally in both populations. Apoptosis could be suppressed and mitogenesis could be induced frequently, however, if irradiated B cells were cultured with B cell activators. When activators using separate signal transduction pathways were compared, a hierarchy of efficiency at effecting apoptosis rescue was observed, and activators used singly without effect could synergize to protect. xid B cells were more resistant to rescue than normal B cells unless PMA was used as a stimulant. Although the mechanism of activator-induced rescue was not established, selective overexpression of a bcl-2 transgene rendered xid B cells radioresistant. The data suggest that a signal(s) delivered to irradiated B cells in the in vivo microenvironment suppresses apoptosis and that xid B cells and a radiosensitive subpopulation of normal B cells are refractory to this signal(s).
Woodland
R T
RT
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester 01655, USA.
Schmidt
M R
MR
Riggs
J E
JE
Korsmeyer
S J
SJ
Lussier
A M
AM
Gravel
K A
KA
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D001402:B-Lymphocytes / Q000276:immunology / Q000528:radiation effects*; D002478:Cells, Cultured; D007109:Immunity; D051379:Mice; D009154:Mutation; D010641:Phenotype; D014916:Whole-Body Irradiation