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 Cgamma1 cluster, the 3' Vgamma3 gene (closest to Jgamma1) rearranges preferentially in the fetal period whereas rearrangement of the 5' Vgamma2 gene predominates in the adult. Reversing the positions of the Vgamma2 and Vgamma3 genes in a genomic transgene resulted in decreased rearrangement of the now 5' Vgamma3 gene in the fetal thymus and increased rearrangement of the now 3' Vgamma2 gene. The reversed rearrangement pattern was not accompanied by significant changes in chromatin accessibility of the relocated Vgamma 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 Vgamma3 rearrangement in favor of Vgamma2 rearrangement.