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

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Science Immunology  14 Dec 2018:
Vol. 3, Issue 30, eaav4036
DOI: 10.1126/sciimmunol.aav4036

γδ T cells come to the fore

Studies on T cells within the tumor microenvironment (TME) have largely focused on T cells that express αβ T cell receptors (TCRs). Using an in vitro culture system to expand melanoma antigen–specific T cells, Benveniste et al. have identified γδ T cells that recognize melanoma antigens in a class I MHC–restricted manner. To understand how these T cells recognize antigens in an MHC-restricted fashion, they crystallized one of these γδ TCRs complexed with cognate peptide, MHC, and β2 microglobulin. Given the success of T cell–centric therapies in cancer, the results presented here call for a closer examination of the role of γδ T cells in the TME of melanomas and other cancers.


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

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