Membrane IgM-stimulated human B lymphocytes succumb to activation-related apoptosis at a G1-->S transition: influence of ligand affinity and valency.
Culture of human B lymphocytes with polyclonally activating surrogates for type II T-cell-independent antigen, i.e., anti-IgM mAb and anti-IgM:dextran, resulted in both membrane IgM (mIgM)-triggered S/G2/M entry and apoptosis. Although high ligand valency could compensate for low affinity, and high affinity could compensate for low valency, in achieving mIgM-triggered apoptosis, the phenomenon was most pronounced when the soluble "antigen" had both high binding site affinity and valency. Most of the mIgM-triggered apoptosis may represent B cells which progress into G1 but fail to receive a sufficient level of continuous mIgM-mediated signaling during G1 for passage through a G1 --> S phase restriction point(s). This was supported by the findings that (a) a lesser proportion of mIg-triggered cells enter S phase than G1; (b) maximal mIgM-triggered apoptosis was noted at 48-72 h of culture and surrounding activated cell clusters; (c) mIgM-triggered apoptosis was not inhibited by pharmacologic blockers of S phase; and (d) a high proportion of viable mIgM-triggered B cell blasts in G1 succumb to apoptosis rather than enter S phase, if high-affinity multivalent ligand is washed from the cultures. In addition to quantitative aspects of initial receptor engagement, the potential for a protracted period of recurrent mIgM signaling events may influence whether apoptosis or cell cycle progression is the functional outcome of B cell encounter with a multivalent antigen.
Department of Rheumatology and Molecular Medicine, Hospital for Joint Diseases, New York, New York, 10003, USA.
P K
PK
Mongini
M A
MA
Vilensky
P F
PF
Highet
J K
JK
Inman
D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology*; D001666:Binding Sites, Antibody; D002453:Cell Cycle; D016193:G1 Phase; D006801:Humans; D007075:Immunoglobulin M / Q000502:physiology*; D037181:Lectins, C-Type; D008024:Ligands; D008213:Lymphocyte Activation; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D016196:S Phase; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007075:Immunoglobulin M; D037181:Lectins, C-Type; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D000099192:CD69 Antigens