V(D)J recombination in the context of B cell

Gnathostomata (/ˌnæθoʊˈstɒmətə/; from Ancient Greek: γνάθος (gnathos) 'jaw' + στόμα (stoma) 'mouth') are jawed vertebrates. Gnathostome diversity comprises roughly 60,000 species, which accounts for 99% of all extant vertebrates, including all living bony fishes (both ray-finned and lobe-finned, including their terrestrial tetrapod relatives) and cartilaginous fishes, as well as extinct prehistoric fish such as placoderms and acanthodians. Most gnathostomes have retained ancestral traits like true teeth, a stomach, and paired appendages (pectoral and pelvic fins, limbs, wings, etc.). Other traits are elastin, horizontal semicircular canal of the inner ear, myelinated neurons, and an adaptive immune system which has discrete lymphoid organs (spleen and thymus) and uses V(D)J recombination to create antigen recognition sites, rather than using genetic recombination in the variable lymphocyte receptor gene.

It is now assumed that Gnathostomata evolved from ancestors that already possessed two pairs of paired fins. Until recently these ancestors, known as antiarchs, were thought to have lacked pectoral or pelvic fins. In addition to this, some placoderms were shown to have a third pair of paired appendages, that had been modified to claspers in males and pelvic basal plates in females — a pattern not seen in any other vertebrate group. The jawless Osteostraci are generally considered the closest sister taxon of Gnathostomata.

Junctional diversity describes the DNA sequence variations introduced by the improper joining of gene segments during the process of V(D)J recombination. This process of V(D)J recombination has vital roles for the vertebrate immune system, as it is able to generate a huge repertoire of different T-cell receptor (TCR) and immunoglobulin molecules required for pathogen antigen recognition by T-cells and B cells, respectively.

Terminal deoxynucleotidyl transferase (TdT), also known as DNA nucleotidylexotransferase (DNTT) or terminal transferase, is a specialized DNA polymerase expressed in immature, pre-B, pre-T lymphoid cells, and acute lymphoblastic leukemia/lymphoma cells. TdT adds N-nucleotides to the V, D, and J exons of the TCR and BCR genes during antibody gene recombination, enabling the phenomenon of junctional diversity. In humans, terminal transferase is encoded by the DNTT gene. As a member of the X family of DNA polymerase enzymes, it works in conjunction with polymerase λ and polymerase μ, both of which belong to the same X family of polymerase enzymes. The diversity introduced by TdT has played an important role in the evolution of the vertebrate immune system, significantly increasing the variety of antigen receptors that a cell is equipped with to fight pathogens. Studies using TdT knockout mice have found drastic reductions (10-fold) in T-cell receptor (TCR) diversity compared with that of normal, or wild-type, systems. The greater diversity of TCRs that an organism is equipped with leads to greater resistance to infection. Although TdT was one of the first DNA polymerases identified in mammals in 1960, it remains one of the least understood of all DNA polymerases. In 2016–18, TdT was discovered to demonstrate in trans template dependant behaviour in addition to its more broadly known template independent behaviour

TdT is absent in fetal liver HSCs, significantly impairing junctional diversity in B-cells during the fetal period.