Human TCR-γ⁺/δ⁺, CD8⁺ T lymphocytes recognize tetanus toxoid in an MHC-restricted fashion

We have analyzed the ability of human γ⁺/δ⁺ T cells to recognize a nominal antigen in association with MHC molecules. A TT-specific T cell line with ~40% γ⁺/δ⁺ T cells was established from a hyperimmunized donor, D.F., by stimulation with antigen and autologous APC. Three DF-derived γ⁺/δ⁺ clones were CD8⁺ as determined by immunofluorescence staining, and by Southern and Northern blotting with probes detecting δ chain rearrangement and δ and γ chain transcripts, respectively. The γ⁺/δ⁺ clones responded to stimulation with TT, but not TNP-BSA, and autologous APC by proliferation and IFN-γ production. No proliferation or IFN-γ production was detected when TT-specific T cell clones were stimulated with either TT or autologous APC only. The response to TT was enhanced by addition of exogenous IL-2. The use of allogeneic APC from 19 donors sharing one HLA-determinant with the autologous donor D.F., showed that the γ⁺/δ⁺ T cells responded to TT with HLA-DR4-related restriction as measured by proliferation and IFN-γ production. These results demonstrate that γ/δ receptors can recognize non-MHC-encoded foreign antigen in a self-MHC-restricted fashion.