Regulation of Tcrb Gene Assembly by Genetic, Epigenetic, and Topological Mechanisms

The adaptive immune system endows mammals with an ability to recognize nearly any foreign invader through antigen receptors that are expressed on the surface of all lymphocytes. This defense network is generated by V(D)J recombination, a set of sequentially controlled DNA cleavage and repair events that assemble antigen receptor genes from physically separated variable (V), joining (J), and sometimes diversity (D) gene segments. The recombination process itself must be stringently regulated to minimize oncogenic translocations involving chromosomes that harbor immunoglobulin and T cell receptor loci. Indeed, V(D)J recombination is controlled at several levels, including tissue-, developmental stage-, allele-, and gene segment-specificity. These levels of control are imposed by a collection of architectural and regulatory elements that are distributed throughout each antigen receptor locus. Together, the genetic elements regulate developmental changes in chromatin, transcription, and locus topology that promote or disfavor long-range recombination. This chapter focuses on the cross talk between these mechanisms at the T cell receptor beta (Tcrb) locus, and how they sculpt a diverse TCRβ repertoire while maintaining monospecificity of this antigen receptor on each mature T lymphocyte. We also discuss how insights obtained from studies of Tcrb are more generally relevant to our understanding of gene regulation strategies employed by mammals.