EBV transformation induces overexpression of hMSH2/3/6 on B lymphocytes and enhances γδT‐cell‐mediated cytotoxicity via TCR and NKG2D

Abstract

The engagement of Epstein-Barr virus (EBV)-induced protein ligands in γδ T-cell-mediated anti-EBV immunity, especially in EBV-associated B-cell malignancies, has not been fully elucidated. Previously we reported the overexpression of human MutS homologue 2 (hMSH2), a stress-inducible protein ligand for human γδ T-cells, on EBV-transformed B lymphoblastic cell lines (B-LCLs). In this study, we first generated EBV-transformed B-LCLs from peripheral blood mononuclear cells of healthy volunteers with B95-8 cellular supernatant and cyclosporine A. Secondly, we demonstrated the significantly elevated cell surface protein expression and mRNA transcription of hMSH2 in EBV-transformed B-LCLs, 3D5 and EBV-positive B lymphoma cell line Daudi and Raji. Thirdly, hMSH2-mediated recognition of EBV-transformed B malignant cells by human γδ T-cells was confirmed by specific antibody blocking and siRNA interference. Both TCRγδ and NKG2D participated in hMSH2-mediated recognition of EBV-transformed B malignant cells. Furthermore, hMSH3 and hMSH6, the companion proteins of hMSH2, along with CD98, were found overexpressed on the surface of EBV-transformed malignant B-cells. We concluded that the induced overexpression of hMSH proteins might serve as early alerting biomarkers emerged in EBV-related B-cell malignances or as potential targets for establishing γδ T-cell-based therapeutic immunotherapies towards EBV infection.

Tumor-associated protein ligands recognized by human γδ T cell receptor and their implications in cancer therapy

“…Our team demonstrated that γδ T cells in peripheral blood could recognize hMSH2 expression on the tumor surface via the TCR and NKG2D. The results of our study demonstrated for the first time that hMSH2 expression on Epstein-Barr virus (EBV)-transformed B cells is upregulated and participates in T cell-mediated antiviral cytotoxicity [70].…”

Protective Role ofγδT Cells in Different Pathogen Infections and Its Potential Clinical Application

“…Human MutS homologue (including hMSH2/3/6), which is one kind of protein for DNA mismatch repair and also as a stress-induced protein ligand, is overexpressed in B lymphoblastic cells. This improves the recognition and effective cytotoxicity function of γδ T cells as well as protein ligands [ 133 ]. Besides, EBNA1 as nuclear antigen (also called latency I) is expressed on EBV-infected memory B cells and is indispensable for replication of viral genome.…”