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 μ and κ transgenes. Deletion was the result of apoptosis. In mice that carried an additional δ transgene sIgD interfered with tolerance induction. The stage in which the cells were sensitive to deletion was characterized as a transitional stage between immature (sIgM(dull), heat-stable antigen(bright), B220(dull), sIgD^-) and more mature (IgM(bright), heat-stable antigen(dull), B22O(bright), 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.