Gene placement and competition control T cell receptor γ variable region gene rearrangement

The production of distinct sets of T cell receptor (TCR) gamma delta(+) T cells occurs in an ordered fashion in thymic development. The V gamma 3 and V gamma 4 genes, located downstream in the TCR gamma C gamma 1 gene cluster, are expressed by the earliest waves of developing TCR gamma delta(+) T cells in the fetal thymus, destined for intraepithelial locations. Upstream V gamma 2 and V gamma 5 genes are expressed in later waves in the adult and constitute most TCR gamma delta(+) T cells in secondary lymphoid tissue. This developmental pattern is caused in part by a preference for rearrangements of the downstream V gamma 3 and V gamma 4 genes in the early fetal stage, which switches to a preference for rearrangements of the upstream V gamma 2 and V gamma 5 gene rearrangements in the adult. Our gene targeting studies show that the downstream V gamma genes rearrange preferentially in the early fetal thymus because of their downstream location, independent of promoter or recombination signal sequences and unrelated to the extent of germline transcription. Remarkably, gene deletion studies show that the downstream V gamma genes competitively inhibit upstream V gamma rearrangements at the fetal stage. These data provide a mechanism for specialization of the fetal thymus for the production of T cells expressing specific V gamma genes.