Ectopically Expressed Human Tumor Biomarker MutS Homologue 2 Is a Novel Endogenous Ligand That Is Recognized by Human γδT Cells to Induce Innate Anti-tumor/Virus Immunity

Human (h) MutS homologue 2, a nuclear protein, is a critical element of the DNA mismatch repair system. Our previous studies suggest that hMSH2 might be a protein ligand for TCR gamma delta. Here, we show that hMSH2 is ectopically expressed on a large panel of epithelial tumor cells. We found that hMSH2 interacts with both TCR gamma delta and NKG2D and contributes to V delta 2 T cell-mediated cytolysis of tumor cells. Moreover, recombinant human MSH2 protein stimulates the proliferation and IFN-gamma secretion of V delta 2 T cells in vitro. Finally, hMSH2 expression is induced on the cell surface of Epstein-Barr virus-transformed lymphoblastoid cell lines, and the induction increases the sensitivity of these lymphoblastoid cell lines to gamma delta T cell-mediated cytolysis. Our data suggest that hMSH2 functions as a tumor-associated or virus infection-related antigen recognized by both V delta 2 TCR and NKG2D, and it plays a role in eliciting the immune responses of gamma delta T cells against tumor-and virus-infected cells. The recognition of ectopic surface-expressing endogenous antigen by TCR gamma delta and NKG2D may be an important mechanism of innate immune response to carcinogenesis and viral infection.