Abstract
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 TCRγδ. Here, we show that hMSH2 is ectopically expressed on a large panel of epithelial tumor cells. We found that hMSH2 interacts with both TCRγδ and NKG2D and contributes to Vδ2 T cell-mediated cytolysis of tumor cells. Moreover, recombinant human MSH2 protein stimulates the proliferation and IFN-γ secretion of Vδ2 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 γδ T cell-mediated cytolysis. Our data suggest that hMSH2 functions as a tumor-associated or virus infection-related antigen recognized by both Vδ2 TCR and NKG2D, and it plays a role in eliciting the immune responses of γδ T cells against tumor- and virus-infected cells. The recognition of ectopic surface-expressing endogenous antigen by TCRγδ and NKG2D may be an important mechanism of innate immune response to carcinogenesis and viral infection.
Highlights
Expressed hMSH2 is a tumor biomarker; the mechanism of its recognition is unclear
We found that hMSH2, normally located in the nucleus, was ectopically expressed on the cell surface of different epithelial tumor cells, and its expression was induced by EBV transformation
To the best of our knowledge, our results provide the first evidence that cell surface-expressed hMSH2 is a ligand for both V␦2 TCR and NKG2D receptors and engages in anti-tumor and anti-virus immunity by enhancing the ␥␦ T cell-mediated cytolysis
Summary
Expressed hMSH2 is a tumor biomarker; the mechanism of its recognition is unclear. Substantial evidence indicates that human ␥␦ T cells have the potential to recognize a diverse set of endogenous antigens/ ligands, such as MHC class I-related chains A and B [5], members of CD1 family [6], UL16-binding proteins (ULBPs)2 [7, 8], heat shock proteins (HSPs) [9], and F1-ATPase-apolipoprotein A-I complex [10] Most of these molecules are either integral membrane proteins [11] or glycosylphosphatidylinositol-anchored proteins [12], typically expressed poorly or not at all by normal cells [12,13,14]. To the best of our knowledge, our results provide the first evidence that cell surface-expressed hMSH2 is a ligand for both V␦2 TCR and NKG2D receptors and engages in anti-tumor and anti-virus immunity by enhancing the ␥␦ T cell-mediated cytolysis.
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