B cell receptor-induced apoptosis in primary transitional murine B cells: signaling requirements and modulation by T cell help.
Self-reactive immature B cells may be eliminated in the bone marrow (BM) after B cell receptor (BCR) engagement in a process known as negative selection. Immature B cells emigrating from the BM, the so-called transitional cells, remain sensitive to negative selection and are likely to be important targets of tolerance towards peripheral antigens. Transitional cells are deleted through apoptosis after BCR cross-linking in vitro. Using anti-Ig as a surrogate antigen, we determined the signaling requirements for the induction of apoptosis in transitional cells. Treatment with anti-Ig for only 20 min causes most cells to be apoptotic 16 h later. Furthermore, apoptosis of transitional cells is induced with low doses of anti-Ig while mature cell proliferation requires extended culture at 30-fold higher concentrations. For both populations of B cells, total surface Ig expression is equivalent, therefore indicating that the threshold of BCR signaling required to elicit these responses is different. T cell help can modulate B cell tolerance. However, specific help may not be available when apoptosis is triggered by a peripheral antigen. The opportunity to reverse apoptosis of transitional cells is surprisingly long. Even 8 h after anti-Ig treatment, IL-4 or anti-CD40 antibody can block apoptosis. The upper time limit of protection is concurrent with irreversibility of apoptosis as measured by DNA fragmentation. These findings indicate that B cell negative selection is more easily triggered than activation, and that the induction of apoptosis and its reversal by T cell help can be events that occur in distinct microenvironments.
Sater
R A
RA
Department of Neurology, University of Pennsylvania, Philadelphia 19104, USA.
Sandel
P C
PC
Monroe
J G
JG
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D019013:CD40 Antigens / Q000502:physiology; D002454:Cell Differentiation; D053938:DNA Fragmentation; D005260:Female; D015847:Interleukin-4 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011947:Receptors, Antigen, B-Cell / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*
D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; D011947:Receptors, Antigen, B-Cell; D015847:Interleukin-4