Positive and Negative Regulation of V(D)J Recombination by the E2A Proteins

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Abstract
A key feature of B and T lymphocyte development is the generation of antigen receptors through the rearrangement and assembly of the germline variable (V), diversity (D), and joining (J) gene segments. However, the mechanisms responsible for regulating developmentally ordered gene rearrangements are largely unknown. Here we show that the E2A gene products are essential for the proper coordinated temporal regulation of V(D)J rearrangements within the T cell receptor (TCR) γ and δ loci. Specifically, we show that E2A is required during adult thymocyte development to inhibit rearrangements to the γ and δ V regions that normally recombine almost exclusively during fetal thymocyte development. The continued rearrangement of the fetal Vγ3 gene segment in E2A-deficient adult thymocytes correlates with increased levels of Vγ3 germline transcripts and increased levels of double-stranded DNA breaks at the recombination signal sequence bordering Vγ3. Additionally, rearrangements to a number of Vγ and Vδ gene segments used predominately during adult development are significantly reduced in E2A-deficient thymocytes. Interestingly, at distinct stages of T lineage development, both the increased and decreased rearrangement of particular Vδ gene segments is highly sensitive to the dosage of the E2A gene products, suggesting that the concentration of the E2A proteins is rate limiting for the recombination reaction involving these Vδ regions.