B cell positive selection by self antigens and counter-selection of dual B cell 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 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.
Lymphocyte Population Biology Unit, URA CNRS 1961, Institut Pasteur, Paris, France. mrosado@pasteur.fr
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Rosado
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Freitas
D000818:Animals; D000941:Antigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D007108:Immune Tolerance; D007075:Immunoglobulin M / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*
D000941:Antigens; D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; C064655:V(D)J recombination activating protein 2