Hypercross-linking surface IgM or IgD receptors on mature B cells induces apoptosis that is reversed by costimulation with IL-4 and anti-CD40.
Cross-linking of sIgM or sIgD receptors on mature B cells with appropriate anti-Ig Abs normally induces B cell activation and DNA synthesis. We show here that hypercross-linking of either class of sIg receptor on these cells by biotinylated, normally mitogenic anti-mu or anti-delta mAb by avidin rapidly induces unresponsiveness to heterologous anti-Ig, accompanied by DNA fragmentation characteristic of apoptosis. Apoptotic nuclei can be detected within 4 h after stimulation, but cells that survive for 12 to 16 h are abortively activated, as evidenced by increased levels of MHC class II Ags. Because the induction of B cell tolerance is known to be modulated by T cell-derived influences, we investigated the effects of two stimuli--IL-4 and ligation of CD40--that are known to affect B cell survival in this system. IL-4 partially reversed the induction of apoptosis, as did a mAb to CD40, and both reagents together caused almost complete reversal. We therefore conclude that in the absence of T cell help the extent of sIg receptor cross-linking on mature B cells determines whether the cells enter cycle or become deleted. We believe that this system represents a polyclonal model of clonal deletion of mature B cells induced by highly cross-linking Ags, such as type 2 T-independent polysaccharide Ags.
Parry
S L
SL
Laboratory of Cellular Immunology, National Institute for Medical Research, Mill Hill, London, UK.
Hasbold
J
J
Holman
M
M
Klaus
G G
GG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology*; D019013:CD40 Antigens; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008954:Models, Biological; D011961:Receptors, Fc / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D011961:Receptors, Fc; C050855:immunoglobulin D receptor; C035311:immunoglobulin M receptor; D015847:Interleukin-4; D004247:DNA