Assembly of TCRα and TCRδ genes from the TCRα/δ locus is tightly controlled for the proper generation of αβ and γδ T cells. Of >100 shared variable gene segments in the TCRα/δ locus, only a few are predominantly used for the TCRδ gene assembly, while most are for TCRα. However, the importance and mechanisms of the selective variable gene rearrangement for T cell development are not fully understood. We report herein that the development of a tissue-specific γδ T cell population is critically affected by recombination signal sequence-associated restriction on the variable gene usage for TCRδ assembly. We found that the development of substitute skin γδ T cells in mice deficient of the TCRγ3 gene, which is used in wild-type skin γδ T cells, was drastically affected by the strain background. A Vγ2+ skin γδ T cell population developed in mice of the B6 but not the 129 strain backgrounds, due to a difference in the rearrangement of endogenous Vδ7+ TCRδ genes, which paired with the Vγ2+ TCRγ gene to generate the Vγ2/Vδ7+ skin γδ T cell precursors in fetal thymi of the B6 background mice. The defective TCRδ rearrangement of the 129-"Vδ7" gene was associated with specific variations in its recombination signal sequence, which renders it poorly compatible for rearrangement to Dδ genes. These findings provide the first direct evidence that recombination signal sequenceassociated restriction on the variable gene usage for TCRα/δ gene assembly plays an important role in T cell development.
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