Recombination Signal Sequence-Associated Restriction on TCRδ Gene Rearrangement Affects the Development of Tissue-Specific γδ T Cells

Assembly of TCR alpha and TCR delta genes from the TCR alpha/delta locus is tightly controlled for the proper generation of alpha beta and gamma delta T cells. Of >100 shared variable gene segments in the TcR alpha/delta locus, only a few are predominantly used for the TCR delta gene assembly, while most are for TCR alpha. 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 gamma delta T cell population is critically affected by recombination signal sequence-associated restriction on the variable gene usage for TCR delta assembly. We found that the development of substitute skin gamma delta T cells in mice deficient of the TCR gamma 3 gene, which is used in wild-type skin gamma delta T cells, was drastically affected by the strain background. A V gamma 2(+) skin gamma delta T cell population developed in mice of the B6 but not the 129 strain backgrounds, due to a difference in the rearrangement of endogenous V delta 7(+) TCR delta genes, which paired with the V gamma 2(+) TCR gamma gene to generate the V gamma 2/V delta 7(+) skin gamma delta T cell precursors in fetal thymi of the B6 background mice. The defective TCR delta rearrangement of the 129-V delta 7 gene was associated with specific variations in its recombination signal sequence, which renders it poorly compatible for rearrangement to D delta genes. These findings provide the first direct evidence that recombination signal sequence-associated restriction on the variable gene usage for TCR alpha/delta gene assembly plays an important role in T cell development. The Journal of Immunology, 2009, 183: 4931-4939.