V(D)J hypermutation and receptor revision: coloring outside the lines.

At least three mechanisms increase potential genetic diversity in peripheral B lymphocytes: hypermutation, gene conversion and secondary V(D)J rearrangements. These diversifying activities were once believed to be strictly confined to the immunoglobulin loci and B cells. Recent experiments demonstrate that this is not the case. Hypermutation has now been shown to diversify the BCL-6 genes of germinal-center B cells. The role, if any, of these mutations in the immune response remains unknown but the notion that the hypermutation mechanism is targeted solely to immunoglobulin genes is no longer tenable. Peripheral T cells may also diversify their antigen receptors by the reactivation of RAG (recombination-activating gene)1 and RAG2 and secondary V(D)J rearrangements. These new findings suggest a remarkable genetic plasticity in subsets of antigen-reactive lymphocytes and may frame new questions of clonal selection and self tolerance.