Control of antigen receptor diversity through spatial regulation of V(D)J recombination.

Lymphocytes recognize a vast variety of pathogens by expressing a diverse repertoire of antigen receptor genes that are assembled by V(D)J recombination in immature B cells (Igh, Igk) and T cells (Tcrb, Tcra /d). V(D)J recombination takes place in the 3' proximal domain containing the D, J, and C gene segments, whereas 31 (Tcrb) to 200 (Igh) V genes arc spread over a large region of 0.67 (Tcrb) to 3 (Igk) Mb pairs. All antigen receptor loci undergo reversible contraction at the developmental stage, where they engage in V-(D)J recombination. This long-range looping promotes the participation of all V genes in V- (D)J recombination by juxtaposing distant V genes next to (D)J segments in the proximal recombination center. The B-cell-specific Pax5, ubiquitous YY1, and architectural CTCF/cohesin proteins promote Igh locus contraction in pm-B cells by binding to multiple sites in the V-H gene cluster. These regulators also control the pro-B-cell-specific activity of the distally located PAIR elements, which are likely involved in the regulation of V-H -DJ(H) recombination by mediating locus contraction. Notably, the large V-H gene cluster of the Igh locus undergoes flexible long-range looping that ensures similar participation of all V-H genes in V-H -DJ(H) recombination to generate a diverse antibody repertoire.