CD40 cross-linking inhibits specific antibody production by human B cells

Ligation of CD40 on B cells is a co-stimulatory signal for proliferation,antibody secretion, heavy chain switching and rescue from apoptosisafter somatic mutation in the germinal centre. The importanceof these manifold responses to CD40 activation for humoral immunityis exemplified by the inability of boys with X-linked hyperIgM syndrome to make IgG, IgE or IgA due to a mutation in inthe gene coding for CD40 ligand (CD40L). In the present study,we have investigated the effect of CD40 ligation on specificantibody production by human B cells to influenza virus. Theantibody. response was T cell dependent and specific for thestrain of influenza virus used as antigen. Addition of eitherCD40 mAb or recombinant trimeric CD40L profoundly inhibitedspecific antibody production. Antibody production by unseparatedtonsillar mononuclear cells and by T-depleted B cells stimulatedwith antigen in the presence of T cell replacing factor wereequally inhibited with CD40 antibody showing that the effectwas due to ligation of CD40 on B cells rather than blockingof T cell help. The specific antibody detected in these experimentswas mostly IgG with little or no IgM and was obtained from surfaceIgM B cells consistent with activation of a secondary (memoryresponse. Co-stimulation of tonsillar B cells with CD40 antibodyand anti-IgG induced proliferation of IgG⁺ B cells. These resultssuggest that CD40 ligation can inhibit specific antibody responsesand stimulate proliferation in the same IgG⁺ (memory) B cellsubpopulation. Addition of CD40 antibody during the first 24–48h of the response was required for inhibition, suggesting thatthe effect was on early B cell activation and/or proliferationrequired for antibody production. There was no correlation,however, between the ability of CD40 mAb to stimulate proliferationand inhibit antibody production. We suggest that early activationof CD40 in the specific antibody response inhibits the formationof plasma cells and promotes instead the generation of memorycells.