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

Assembly of TCR and TCR genes from the TCR / locus is tightly controlled for the proper generation of and T cells. Of >100 shared variable gene segments in the TCR / locus, only a few are predominantly used for the TCR gene assembly, while most are for TCR . 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 T cell population is critically affected by recombination signal sequence-associated restriction on the variable gene usage for TCR assembly. We found that the development of substitute skin T cells in mice deficient of the TCR 3 gene, which is used in wild-type skin T cells, was drastically affected by the strain background. A V 2 skin 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 7 TCR genes, which paired with the V 2 TCR gene to generate the V 2/V 7 skin T cell precursors in fetal thymi of the B6 background mice. The defective TCR rearrangement of the 129-“V 7” gene was associated with specific variations in its recombination signal sequence, which renders it poorly compatible for rearrangement to D genes. These findings provide the first direct evidence that recombination signal sequenceassociated restriction on the variable gene usage for TCR / gene assembly plays an important role in T cell development. The Journal of Immunology, 2009, 183: 4931–4939.