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

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 expres s chains from the two transgenes. We studied selection of these dual recept or B cells in the presence of self antigens. In spite of the reduced surfac e density of the anti-self receptor, self-reactive B cells are deleted in t he presence of membrane-bound self antigens. In contrast, the presence of s oluble self antigen positively selects single receptor B cells expressing t he self-reactive receptor. At the periphery these positively selected B cel ls down-regulate surface IgM expression and become unresponsive. A few dual receptor cells, however, escape tolerance induction. We examined the perip heral fate of the dual receptor B cells and showed that they are poorly sel ected into the activated B cell compartment and show a poor competitive cap acity when in presence of populations of single receptor B cells. These res ults indicate that peripheral selection contributes to the very low frequen cies of dual receptor B cells in normal mice and that multiple safeguard me chanisms operate to minimize the autoimmune hazard that allelically include d B cells could represent.