Entry of B cell receptor into signaling domains is inhibited in tolerant Bcells

Signal transduction through the B cell antigen receptor (BCR) is altered in B cells that express a receptor that recognizes self-antigen. To understan d the molecular basis for the change in signaling in autoreactive B cells, a transgenic model was used to isolate a homogeneous population of tolerant B lymphocytes. These cells were compared with a similar population of naiv e B lymphocytes. We show that the BCR from naive B cells enters a detergent -insoluble domain of the cell within 6 s after antigen binding, before a de tectable increase in BCR phosphorylation. This fraction appears to be impor tant for signaling because it is enriched for lyn kinase but lacks CD45 tyr osine phosphatase and because the BCR that moves into this domain becomes m ore highly phosphorylated. Partitioning of the BCR into this fraction is un affected by src family kinase inhibition. Tolerant B cells do not efficient ly partition the BCR into the detergent-insoluble domain, providing an expl anation for their reduced tyrosine kinase activation and calcium nux in res ponse to antigen. These results identify an early, regulated step in antige n receptor signaling and self-tolerance.