Essential Contribution of Germline-Encoded Lysine Residues in Jγ1.2 Segment to the Recognition of Nonpeptide Antigens by Human γδ T Cells

Human γδ T cells display unique repertoires of Ag specificities largely imposed by selective usages of distinct Vγ and Vδ genes. Among them, Vγ2/Vδ2+ T cells predominate in the circulation of healthy adults and respond to various microbial small molecular mass nonpeptide Ags. The present results indicate that the primary Vγ2/Vδ2+ T cells stimulated with the distinct groups of nonpeptide Ags, including monoethyl pyrophosphate, isobutyl amine, and aminobisphosphonate, invariably exhibit Jγ1.2 in the Vγ2+ TCR-γ chains. Gene transfer studies revealed that most of the randomly cloned Vγ2/Jγ1.2+ TCR-γ genes bearing diverse Vγ/Jγ junctional sequences could confer the responsiveness to all these nonpeptide Ags, while none of the Vγ2/Jγ1.1+ or Vγ2/Jγ1.3+ TCR-γ genes could do so. Furthermore, mutation of the lysine residues encoded by the Jγ1.2 gene, which are unique in human Jγ1.2 and absent in other human or mouse Jγ segments, completely abrogated the responsiveness to all the nonpeptide Ags without affecting the response to anti-CD3 mAb. These results strongly suggested that the positively charged lysine residues in the TCR-γ chain CDR3 region encoded by the germline Jγ1.2 gene play a key role in the recognition of diverse small molecular mass nonpeptide Ags.