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.

Author Info: (1) Sunnybrook Research Institute, Toronto, ON, Canada. (2) Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA. (3) Princess Margaret Cancer Center

Author Info: (1) Sunnybrook Research Institute, Toronto, ON, Canada. (2) Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA. (3) Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. (4) Sunnybrook Research Institute, Toronto, ON, Canada. (5) Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. (6) Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. (7) Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. (8) Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. Department of Immunology, University of Toronto, Toronto, ON, Canada. (9) Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA. jczp@sri.utoronto.ca ejadams@uchicago.edu. (10) Sunnybrook Research Institute, Toronto, ON, Canada. jczp@sri.utoronto.ca ejadams@uchicago.edu. Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. Department of Immunology, University of Toronto, Toronto, ON, Canada.

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