Membrane IgD and membrane IgM differ in capacity to transduce inhibitory signals within the same human B cell clonal populations.

The relative capacity of two coexpressed membrane Ig (mIg) isotypes, mIgM and mIgD, to actively transduce tolerogenic signals was evaluated with three human B cell leukemic clonal populations. Although anti-IgM mAb directed to various domains of the mIgM molecule suppressed spontaneous or T cell factor-induced leukemic DNA synthesis at concentrations as low as 0.01 to 0.1 microgram/ml, anti-IgD antibodies of both monoclonal and polyclonal origin failed to inhibit at doses as high as 100 micrograms/ml. Several possibilities for the differential capacity of mIgM and mIgD molecules to signal inhibition in these leukemic clonal populations were evaluated. Differences in the intrinsic membrane expression of the two isotypes before in vitro clonal activation were not responsible because the above distinctions were noted in cells of a chronic lymphocytic leukemia, which expressed slightly more mIgD than mIgM. The ineffective inhibitory signaling capacity of mIgD-specific ligands was also not caused by a selective decrease in the membrane expression of mIgD during cell culture, because the density of each isotype remained relatively constant during the first 44 h of in vitro activation by T cell factors, and following capping, mIgM and mIgD were resynthesized with similar kinetics. Because anti-IgM and anti-IgD mAb with comparable affinities for their respective membrane molecules differed significantly in inhibitory potential, it was considered improbable that the IgD-specific ligands tested bound to mIgD with a suboptimal affinity for inducing tolerance. Inhibition of leukemic DNA synthesis was observed after incubation with either anti-kappa antibody or a mixture of IgM- and IgD-isotype-specific antibodies, indicating that cross-linking of mIgD does not make B cell clones refractory to tolerogenic signal transduction through mIgM. These studies provide strong clonal support for the concept that coexpressed mIgM and mIgD molecules play distinct roles in human B cell immunoregulation.