Negative selection of human germinal center B cells by prolonged BCR cross-linking.
The antigen receptors on T and B lymphocytes can transduce both agonist and antagonist signals leading either to activation/survival or anergy/death. The outcome of B lymphocyte antigen receptor (BCR) triggering depends upon multiple parameters which include (a) antigen concentration and valency, (b) duration of BCR occupancy, (c) receptor affinity, and (d) B cell differentiation stages. Herein, using anti-immunoglobulin kappa and lambda light chain antibodies, we analyzed the response of human naive, germinal center (GC) or memory B cells to BCR cross-linking regardless of heavy chain Ig isotype or intrinsic BCR specificity. We show that after CD40-activation, anti-BCR (kappa + gamma) can elicit an intracellular calcium flux on both GC and non-GC cells. However, prolonged BCR cross-linking induces death of CD40-activated GC B cells but enhances proliferation of naive or memory cells. Anti-kappa antibody only kills kappa + GC B cells without affecting surrounding gamma + GC B cells, thus demonstrating that BCR-mediated killing of GC B lymphocytes is a direct effect that does not involve a paracrine mechanism. BCR-mediated killing of CD40-activated GC B cells could be partially antagonized by the addition of IL-4. Moreover, in the presence of IL-4, prestimulation through CD40 could prevent subsequent anti-Ig-mediated cell death, suggesting a specific role of this combination in selection of GC B cells. This report provides evidence that in human, susceptibility to BCR killing is regulated along peripheral B cell differentiation pathway.
Galibert
L
L
Schering-Plough, Laboratory for Immunological Research, Dardilly, France.
Burdin
N
N
Barthélémy
C
C
Meffre
G
G
Durand
I
I
Garcia
E
E
Garrone
P
P
Rousset
F
F
Banchereau
J
J
Liu
Y J
YJ
D000888:Antibodies, Anti-Idiotypic; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D002469:Cell Separation; D003432:Cross-Linking Reagents; D018858:Germinal Center / Q000276:immunology; D006801:Humans; D007132:Immunoglobulin Isotypes; D007145:Immunoglobulin kappa-Chains / Q000276:immunology; D007146:Immunoglobulin lambda-Chains / Q000276:immunology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology
D000888:Antibodies, Anti-Idiotypic; D015703:Antigens, CD; D019013:CD40 Antigens; D003432:Cross-Linking Reagents; D007132:Immunoglobulin Isotypes; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D007376:Interleukin-2; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D015847:Interleukin-4; D007371:Interferon-gamma