V(D)J Recombination: Mechanism, Errors, and Fidelity

The realization, now more than half a century ago, that B cells can generate antibodies to an astounding variety of chemical structures sparked intense interest in the "generation of diversity" question (reviewed in reference1). The correct solution to this puzzle turned out to be both surprising and simple: the exons encoding the antigen-binding portions of the receptor (the so-called variable regions) are assembled by chromosomal breakage and rejoining in developing lymphocytes (2). Immunoglobulins and T-cell receptors are composed of two polypeptide chains, each of which contributes to the antigen-binding domain. The exons encoding the antigen-binding domains are assembled from so-called V (variable), D (diversity), and J (joining) gene segments by "cut and paste" DNA rearrangements. This process, termed V(D)J recombination, chooses a pair of segments, introduces double-strand breaks adjacent to each segment, deletes (or, in selected cases, inverts) the intervening DNA, and ligates the segments together (Fig. 1). Rearrangements occur in an ordered fashion, with D-to-J joining proceeding before a V segment is joined to the rearranged D-J segments. This process of combinatorial assembly—choosing one segment of each type from several (sometimes many) possibilities—is the fundamental engine driving antigen-receptor diversity in mammals. Diversity is tremendously amplified by the characteristic variability at the junctions (loss or gain of small numbers of nucleotides) between the various segments. This process leverages a relatively small investment in germline coding capacity into an almost limitless repertoire of potential antigen-binding specificities.