Mechanics of T cell receptor gene rearrangement

Abstract

The four T cell receptor genes (Tcra, Tcrb, Tcrg, Tcrd) are assembled by V(D)J recombination according to distinct programs during intrathymic T cell development. These programs depend on genetic factors, including gene segment order and recombination signal sequences. They also depend on epigenetic factors. Regulated changes in chromatin structure, directed by enhancers and promoter, can modify the availability of recombination signal sequences to the RAG recombinase. Regulated changes in locus conformation may control the synapsis of distant recombination signal sequences, and regulated changes in subnuclear positioning may influence locus recombination events by unknown mechanisms. Together these influences may explain the ordered activation and inactivation of T cell receptor locus recombination events and the phenomenon of Tcrb allelic exclusion.

Figure 1

Structure and organization of TCR loci. Regulatory elements discussed in the text are identified above each diagram, and gene segments are identified below each diagram. Promoters are depicted by bent arrows and enhancers by ovals. Not shown in the diagram of Tcrg is the nonfunctional C_γ3 cluster. The diagram of Tcra/Tcrd identifies several of the most commonly used V_δ gene segments (TRDV2-2, TRDV4, TRDV5, TRAV15). Diagrams of the loci are not drawn to scale and for Tcra/Tcrd the diagram does not accurately reflect the number of V or J gene segments.