The genomic arrangement of T cell receptor variable genes is a determinant of the developmental rearrangement pattern

Developmentally regulated V(D)J recombination profoundly influences immune repertoires, but the underlying mechanisms are poorly understood. In the endogenous T cell receptor Cγ1 cluster, the 3′ Vγ3 gene (closest to Jγ1) rearranges preferentially in the fetal period whereas rearrangement of the 5′ Vγ2 gene predominates in the adult. Reversing the positions of the Vγ2 and Vγ3 genes in a genomic transgene resulted in decreased rearrangement of the now 5′ Vγ3 gene in the fetal thymus and increased rearrangement of the now 3′ Vγ2 gene. The reversed rearrangement pattern was not accompanied by significant changes in chromatin accessibility of the relocated Vγ genes. The results support a model in which the 3′ location is the key determinant of rearrangement in the fetus, after which there is a promoter-dependent inactivation of Vγ3 rearrangement in favor of Vγ2 rearrangement.