Dynamic regulation of antigen receptor gene assembly.

A hallmark feature of adaptive immunity is the production of lymphocytes bearing an enormous repertoire of receptors for foreign antigens. This repertoire is generated early in B and T-cell development by the process of V(D)J recombination, which randomly assembles functional immunoglobulin (Ig) and T-cell receptor (TCR) genes from large arrays of DNA segments. Precursor lymphocytes must target then retarget a single V(D)J recombinase enzyme to distinct regions within antigen receptor loci to guide lymphocyte development and to ensure that each mature B and T-cell expresses only a single antigen receptor specificity. Proper targeting of V(D)J recombinase is also essential to avoid chromosomal aberrations that result in lymphoid malignancies. Early studies suggested that changes in the specificity of V(D)J recombination are achieved by differentially opening or closing chromatin associated with Ig and TCR gene segments at the proper developmental time point. This accessibility model has been extended significantly in recent years and it has become clear that control mechanisms governing antigen receptor gene assembly are multifaceted and vary from locus to locus. In this chapter we review how genetic and epigenetic mechanisms as well as widespread changes in chromosomal conformation synergize to orchestrate the diversification of genes encoding B and T-cell antigen receptors.