A role for immunoglobulin D: interference with tolerance induction.

We have studied the induction and maintenance of tolerance in the B lymphocyte compartment. Neonatal and adult transgenic mice which expressed either surface IgM (sIgM) or sIgM and sIgD anti-2,4,6-trinitrophenyl (TNP) were treated with soluble mono- and multivalent forms of TNP-modified carriers. We compared the B cell compartment of mice treated with antigen and of littermates injected with phosphate-buffered saline. Antigen-mediated cross-linking of membrane-bound IgM (sIgM) caused deletion of B cells both in neonatal and adult mice with mu and kappa transgenes. Deletion was the result of apoptosis. In mice that carried an additional delta transgene sIgD interfered with tolerance induction. The stage in which the cells were sensitive to deletion was characterized as a transitional stage between immature (sIgMdull, heat-stable antigenbright, B220dull, sIgD-) and more mature (IgMbright, heat-stable antigendull, B220bright, sIgD-) B cells. Surviving cells were functional as measured by receptor-mediated changes in the intracellular free Ca2+ concentration. We propose that when the immature B cells have reached the final stages of maturation IgM always transmits negative signals in the absence of T cell help. When B cells need to be screened against self reactivity IgM is the only antigen receptor expressed. The presence of sIgD protects resting B cells from deletion and allows them to initiate an effective immune response.