Abstract
During the recombination of variable (V) and joining (J) gene segments at the T cell receptor α locus, a VαJα joint resulting from primary rearrangement can be replaced by subsequent rounds of secondary rearrangement that use progressively more 5′ Vα segments and progressively more 3′ Jα segments. To understand the mechanisms that target secondary T cell receptor α recombination, we studied the behavior of a T cell receptor α allele (HYα) engineered to mimic a natural primary rearrangement of TRAV17 to Jα57. The introduced VαJα segment was shown to provide chromatin accessibility to Jα segments situated within several kilobases downstream and to suppress germ-line Jα promoter activity and accessibility at greater distances. As a consequence, the VαJα segment directed secondary recombination events to a subset of Jα segments immediately downstream from the primary rearrangement. The data provide the mechanistic basis for a model of primary and secondary T cell receptor α recombination in which recombination events progress in multiple small steps down the Jα array.