The defense mechanism of our adaptive immune system relies on the antigen-recognition abilities of two molecules: T cell receptors (TCRs), attached to the surface of T cells, and immunoglobins (Igs), anchored to and secreted by B cells. These molecules are equipped with pockets that bind with remarkable selectivity to a specific antigen. Our bodies maintain an estimated 10¹⁴ specificities for Igs and a whopping 10¹⁸ for TCRs. Considering our entire genome harbors approximately 10⁵ genes, how is this diversity achieved?

The key lies in the two-protein complex RAG recombinase, which orchestrates a cut-and-paste shuffling of a vast array of pre-existing variable (V), diversity (D), and joining (J) genes in developing B and T cells. Through its catalytic component RAG1, illustrated to the right in the nuclei of REH cells, the rag recombinase recognizes specific DNA sequences positioned at the boundaries of V, D, and J segments called Recombination Signal Sequences (RSS). Stabilized by RAG2, RAG1 nicks the top strand upstream of the RSS, leaving a hydroxyl group free to attack the bond of the opposite strand to produce a double stranded break. This cleavage event occurs in partnership with a matching RSS, creating a gene segment with four ends: two coding hairpins, and two blunt ends. Cellular repair machinery then opens these gene segments, and upon RAG recombinase-mediated histone ubiquitination, enzymes involved in non-homologous end joining (NHEJ) glue the two coding ends together. The result is a rearranged combination of V, D, and J segments that constitutes the antigen-binding part of TCR and Ig molecules.

Coupled with junctional diversity introduced during recombination, this process, directed by the RAG recombinase, contributes to the expansive repertoire of antigen receptors that enables our bodies to recognize and eliminate foreign pathogens.