TEMPORAL AND LINEAGE-SPECIFIC CONTROL OF T-CELL RECEPTOR ALPHA DELTA-GENE REARRANGEMENT BY T-CELL RECEPTOR ALPHA-ENHANCER AND DELTA-ENHANCER/

To analyze the regulation of gene rearrangement at the T cell receptor (TCR) alpha/delta locus during T cell development, we generated trans genic mice carrying a human TCR delta gene minilocus. We previously sh owed that the presence of the TCR delta enhancer (E delta) within the J delta 3-C delta intron was required to activate a specific step (V-D to J) of transgene rearrangement, and that rearrangement was activate d equivalently in the precursors of alpha beta and gamma delta T cells . To further explore the role of transcriptional enhancers in establis hing the developmental pattern of gene rearrangement at the TCR alpha/ delta locus, we substituted the TCR alpha enhancer (E(alpha)) in place of E(delta) within the transgenic minilocus. We found that V-D-J rear rangement of the E(alpha)(+) minilocus was restricted to the alpha bet a T cell subset. Further, we found that although V-D-J rearrangement o f the E(delta)(+) minilocus was initiated in the fetal thymus by day 1 4.5, V-D-J rearrangement of the E(alpha) (+) minilocus did not occur u ntil fetal day 16.5. Finally, whereas V-D-J rearrangement of the E(del ta) (+) minilocus is essentially completed within the triple negative population of postnatal thymocytes, V-D-J rearrangement of the E(alpha )(+) minilocus is only initiated late within this population. Since th e properties of minilocus rearrangement under the control of E(delta) and E(alpha) parallel the properties of V delta-D delta-J delta and V alpha-J alpha rearrangement at the endogenous TCR alpha/delta locus, w e conclude that these enhancers play an important role in orchestratin g the developmental program of rearrangements at this locus.