V(D)J recombination and the evolution of the adaptive immune system.

The immune system needs to be able to identify and ultimately destroy foreign invaders. To do so, it utilizes two major types of immune cells, T cells and B cells (or, collectively, lymphocytes). Lymphocytes display a large variety of cell surface receptors that can recognize and respond to an unlimited number of pathogens, a feature that is the hallmark of the “adaptive” immune system. To react to such a variety of invaders, the immune system needs to generate vast numbers of receptors. If the number of different types of receptors present on lymphocytes were encoded by individual genes, the entire human genome would have to be devoted to lymphocyte receptors. To establish the necessary level of diversity, B- and T-cell receptor (BCR and TCR, respectively) genes are created by recombining preexisting gene segments. Thus, different combinations of a finite set of gene segments give rise to receptors that can recognize unlimited numbers of foreign invaders. This is accomplished by a supremely well-coordinated set of reactions, starting with cleaving DNA within specific, well-conserved recombination signal sequences (RSSs). This highly regulated step is carried out by the lymphocyte-specific recombinationactivating genes (RAG1 and RAG2). The segments are then reassembled using a common cellular repair mechanism. For foreign invaders and their proteins (antigens) that are not part of the host to elicit an immune response, the immune system must be able to recognize countless numbers of antigens. For obvious reasons, an unlimited number of unique antigen receptors cannot be genetically encoded. Rather, the necessary diversity in receptors is achieved by creating variations in the antigen-recognition regions of the receptors of both B cells and T cells. These regions are created by the pairing of two different protein segments, called polypeptide chains (heavy [H] and light [L] chains in the case of the BCR and α and β chains in the case of the TCR), which form a cleft that provides a binding site for the antigen. The mechanism that generates variation in the antigen-binding pockets of these receptors involves mixing and matching variable (V), diversity (D), and joining (J) gene segments in a process called V(D)J recombination. To assemble a single functional receptor, preexisting V, D, and J gene segments are rearranged to yield a contiguous V(D)J region, just upstream of another element of the receptor, the constant (C) region (Figure 1A). Figure 1 V(D)J Recombination Takes Place within the BCR and TCR Loci The BCR H chain and the TCR β chain consist of V, D, and J segments, while BCR L chains and the TCR α chain are comprised of only V and J segments. The number of each type of segments within the chains allows for a large but finite combinatorial possibility in rearrangement, a phenomenon termed combinatorial diversity (Table 1). However, variations generated by V(D)J recombination are uncountable because they do not simply rely on the number of gene segments. Further diversity is introduced because the junctions between rearranged gene segments contain small insertions and deletions (junctional diversity). Finally, both BCR and TCR are heterodimers (consisting of two unmatched polypeptides), so the possibilities of different pairing between the chains can also increase variation. Successful V(D)J rearrangement is clearly useful in terms of antigen recognition, and it is absolutely required for the development and survival of B and T cells. Table 1 Diversification of BCRs and TCRs