Enforcing order within a complex locus: current perspectives on the control of V(D)J recombination at the murine T‐cell receptor α/δ locus

Summary: V(D)J recombination proceeds according to defined developmental programs at T‐cell receptor (TCR) and immunoglobulin loci as a function of cell lineage and stage of differentiation. Although the molecular details are still lacking, such regulation is thought to occur at the level of accessibility of chromosomal recombination signal sequences to the recombinase. The unique and complex organization of the TCRα/δ locus poses intriguing regulatory challenges in this regard: embedded TCRα and TCRδ gene segments rearrange at distinct stages of thymocyte development, there is a highly regulated progression of primary followed by secondary rearrangements involving Jα segments, and there are important developmental constraints on V gene segment usage. The locus therefore provides a fascinating laboratory in which to explore the basic mechanisms underlying developmental control. We provide here a current view of cis ‐acting mechanisms that enforce the TCRα/δ locus developmental program, and we emphasize the unresolved issues that command the attention of our and other laboratories.