Benveniste and Roy et al. were able to generate classical MHC-restricted γδ T cells from hematopoietic stem/progenitor cells and to detect such cells in the naive peripheral human T cell repertoire. Transfer of a melanoma-associated antigen MART-1-specific γδ TCR to Jurkat cells confirmed that activation of these cells was HLA-A2/MART-1-restricted. The affinity ranges of γδ TCRs to HLA-A2/MART-1 were similar to those of αβ TCRs. Crystal structures revealed both similarities and differences between binding of γδ TCRs versus αβ TCRs to HLA-A2/MART-1.
Antigen recognition by T cells bearing alphabeta T cell receptors (TCRs) is restricted by major histocompatibility complex (MHC). However, how antigens are recognized by T cells bearing gammadelta TCRs remains unclear. Although gammadelta T cells can recognize nonclassical MHC, it is generally thought that recognition of antigens is not MHC restricted. Here, we took advantage of an in vitro system to generate antigen-specific human T cells and show that melanoma-associated antigens, MART-1 and gp100, can be recognized by gammadelta T cells in an MHC-restricted fashion. Cloning and transferring of MART-1-specific gammadelta TCRs restored the specific recognition of the initial antigen MHC/peptide reactivity and conferred antigen-specific functional responses. A crystal structure of a MART-1-specific gammadelta TCR, together with MHC/peptide, revealed distinctive but similar docking properties to those previously reported for alphabeta TCRs, recognizing MART-1 on HLA-A*0201. Our work shows that antigen-specific and MHC-restricted gammadelta T cells can be generated in vitro and that MART-1-specific gammadelta T cells can also be found and cloned from the naive repertoire. These findings reveal that classical MHC-restricted human gammadelta TCRs exist in the periphery and have the potential to be used in developing of new TCR-based immunotherapeutic approaches.