Immunology Featured Research Skok Lab

B and T cells express lineage-specific antigen receptors that mediate humoral and cellular immunity, respectively. Immunity depends upon the regulated recombination of variable (V), diversity (D), and joining (J) gene-segments at B cell receptor (BCR) and T cell receptor (TCR) loci to generate sufficient receptor diversity to enable recognition of a near-limitless array of potential antigens. Each antigen receptor consists of heavy and light chains, each of which are encoded by distinct loci. Regulation of accessibility is exerted at a number of levels to ensure lineage specificity and sequential rearrangement of gene-segments at immunoglobulin heavy chain (Igh) and light chain (Igk and Igl) loci.

Allelic exclusion, the process through which successful production of one Ig chain suppresses further rearrangement at the other allele of the same Ig locus, forms an integral part of this regulation and ensures clonality and monospecific recognition by the B cell receptor on individual lymphocytes—a basic tenet of the acquired immune response.

Recent research from the Skok Lab builds on the knowledge that repositioning of loci to pericentromeric heterochromatin, a repressive subcompartment of the nucleus, plays a role in establishing and maintaining allelic exclusion of all Ig loci. In addition, decontraction of the Igh locus contributes to allelic exclusion by physically separating distal and middle VH gene segments from the proximal D-J domain of the locus, thereby preventing further synapse formation and ongoing rearrangement between these regions.

Using 3-dimensional DNA fluorescence in situ hybridization (FISH), the Skok lab identified a lineage- and stage-specific interchromosomal association between the Igh and Igk loci which marks the transition between Igh and Igk recombination. Co-localization occurred between pericentromerically located alleles in pre-B cells, and was mediated by the 3' Igk enhancer. The data indicate a surprising role for the Igk locus and its 3' enhancer in directing the Igh locus to a repressive nuclear subcompartment, and in inducing Igh locus decontraction.

Figure: Confocal section of Igh and Igk loci interaction. Adapted by permission from Macmillan Publishers Ltd: Nature Immunology, advance online publication 24 Feb 2008 (doi:10.1038/ni1567) © 2008.