Engagement of CD40 lowers the threshold for activation of resting B cells via antigen receptor

Cross‐linking of surface Ig (sIg) on resting B cells can generate intracellular signals; however, for T‐dependent antigens to promote growth and differentiation additional surface receptors must be engaged. Ligation of CD40 can stimulate B cell proliferation in the presence of interleukin‐4. A recently identified counterstructure for CD40 is found on T helper cells and is believed to represent the cognate ligand for B cell activation. This study investigates the role of CD40 as an accessory molecule in sIg‐dependent B cell activation. Simultaneous ligation of sIg and CD40 by monoclonal antibodies (mAb) in the presence of mouse L cells which express human Fey receptor type II (FcγRII‐L cells) results in potent stimulation of small resting B cells. When CD40 is co‐ligated, picomolar concentrations of mouse IgG1 anti‐μ, and anti‐δ mAb can stimulate B cell proliferation. This requires interaction of the anti‐Ig mAb with the FcγRII‐L cells: a mouse IgG2a anti‐μ, mAb which is not recognized by FcγRII, was ≥ 1000‐fold less effective. These findings suggest a mechanism for B cell activation whereby engagement of T cells via CD40 and its cognate ligand provides potent enhancement of signals delivered through sIg. Based on these observations, models for the activation of B cells by T‐dependent antigens are presented.