B cell positive selection by self antigens and counter-selection of dual B cell receptor cells in the peripheral B...

The presence of B cells expressing two B cell receptors (BCR), described in BCR-transgenic, gene-targeted and normal mice, may represent an autoimmune hazard. We generated RAG-2-deficient mice bearing two complete rearranged immunoglobulin transgenes. In these mice most mature resting B cells express chains from the two transgenes. We studied selection of these dual receptor B cells in the presence of self antigens. In spite of the reduced surface density of the anti-self receptor, self-reactive B cells are deleted in the presence of membrane-bound self antigens. In contrast, the presence of soluble self antigen positively selects single receptor B cells expressing the self-reactive receptor. At the periphery these positively selected B cells down-regulate surface IgM expression and become unresponsive. A few dual receptor cells, however, escape tolerance induction. We examined the peripheral fate of the dual receptor B cells and showed that they are poorly selected into the activated B cell compartment and show a poor competitive capacity when in presence of populations of single receptor B cells. These results indicate that peripheral selection contributes to the very low frequencies of dual receptor B cells in normal mice and that multiple safeguard mechanisms operate to minimize the autoimmune hazard that allelically included B cells could represent.