Dynamic regulation of antigen receptor gene assembly

Ahallmark feature of adaptive immunity is the production of lymphocytes bearingan enormous repertoire of receptors for foreign antigens. This repertoire is generated early in Band 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 artays of DNA segments. Precursor lymphocytes must target then retarget a single V(D)J recombinaseenzyme to distinct regions with in antigen receptor loci to guide lymphocyte development and to ensure that each mature Band T-cellexpresses only a single antigen receptor specificity. Proper targeting of V(D)J recombinaseis alsoessentialto avoid chromosomal aberrations that result in lymphoid malignancies. Early studies suggested that changesin the specificity of V(D)J recombination are achievedby differentially openingor closing chromatin associated with Ig and TCR genesegments at the proper developmentaltime point. This accessibility model has been extended significantly in recent yearsand it has becomeclear that control mechanismsgoverningantigen receptor gene assembly are multifaceted and vary from locus to locus. In this chapter were view how genetic and epigenetic mechanisms as well as widespread changes in chromosomal conformation synergize to orchestrate the diversification of genes encoding Band T-cell antigen receptors.