Generation and molecular recognition of melanoma-associated antigen-specific human γδ T cells

Antigen recognition by T cells bearing alpha beta T cell receptors (TCRs) is restricted by major histocompatibility complex (MHC). However, how antigens are recognized by T cells bearing gamma delta TCRs remains unclear. Although gamma delta 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 gamma delta T cells in an MHC-restricted fashion. Cloning and transferring of MART-1-specific gamma delta 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 gamma delta TCR, together with MHC/peptide, revealed distinctive but similar docking properties to those previously reported for alpha beta TCRs, recognizing MART-1 on HLA-A*0201. Our work shows that antigen-specific and MHC-restricted gamma delta T cells can be generated in vitro and that MART-1-specific gamma delta T cells can also be found and cloned from the naive repertoire. These findings reveal that classical MHC-restricted human gamma delta TCRs exist in the periphery and have the potential to be used in developing of new TCR-based immunotherapeutic approaches.