A SELECTIVE DEFECT IN IGM ANTIGEN RECEPTOR SYNTHESIS AND TRANSPORT CAUSES LOSS OF CELL-SURFACE IGM EXPRESSION ON TOLERANT B-LYMPHOCYTES

To explore the biochemical basis for maintaining immunological toleran ce by functional inactivation of self-reactive B lymphocytes, transgen ic mice carrying rearranged anti-lysozyme immunoglobulin transgenes an d a lysozyme transgene were used as a source of large numbers of toler ant self-reactive B cells. Antigen receptors of the IgD isotype were e xpressed at normal levels on tolerant B cells, contained the heterodim eric MB1/B29 signalling component of the receptor complex and were str ucturally indistinguishable from IgD on nontolerant B cells. In contra st, cell surface expression of IgM receptor complexes on tolerant B ce lls was greatly reduced, despite normal expression of mRNA encoding th e receptor components. Three-fold fewer immunoreactive mu heavy chains were detectable after a short period of biosynthetic labelling and th e immunoreactive mu chains produced were paired with kappa light chain s and assembled normally into intact receptor complexes containing the MB1/B29 heterodimer. Nascent IgM receptor complexes nevertheless fail ed to be processed into an endoglycosidase H-resistant form in the tol erant B cells and thus appeared to be selectively blocked in their tra nsport from the endoplasmic reticulum to the medial Golgi. These findi ngs demonstrate that intracellular trafficking of antigen receptor com plexes is regulated by exposure to receptor stimuli at the cell surfac e causing a long-lasting decrease in surface receptor expression on to lerant B cells.