Allelic differences in TCR γ-chains alter γδ T cell antigen reactivity

Mouse γδ T cell hybridomas from various strains that express a TCR- Vγ1/Vδ6 respond weakly to an autologous Ag and more strongly to a short segment of the mycobacterial heat shock protein-60 (HSP-60). However, Vγ1/Vδ6 hybridomas derived from AKR mice show greatly reduced or absent responses to these stimuli. To determine whether the lack of response in these AKR hybridomas is caused by polymorphisms found in the expressed AKR γ and TCR-δ genes or, instead, stems from other genes in AKR, we crossed an AKR mouse with a responder mouse, C57B1/10 (B10), and prepared hybridomas from F₁ progeny. Expression of an AKR Vγ1-Jγ4-Cγ4 gene correlated with nonresponsiveness, whereas expression of a B10 Vγ1-Jγ4-Cγ4 gene in most hybridomas ensured responses to both self Ag and the HSP-60 peptide. An allelic difference in the expressed Vδ6 gene was irrelevant to these responses. Moreover, transfection of a functional B10 Vγ1-Jγ4-Cγ4 gene into an F₁ hybridoma variant that had lost the AKR version of this gene restored responses. The allelic γ gene products differ at nine amino acids in the V region, and three amino acids in the C region. In addition, the AKR Cγ4 region contains a 16-amino acid insertion. We propose that amino acid differences among those encoded by the AKR Vγ1-Jγ4-Cγ4 gene are responsible for the lack of response, and reduce the ability of the TCR-γδ to bind the relevant Ag.