Abstract
The common pathogen Epstein-Barr virus (EBV) transforms normal human B cells and can cause cancer. Latent membrane protein 2A (LMP2A) of EBV supports activation and proliferation of infected B cells and is expressed in many types of EBV-associated cancer. It is not clear how latent EBV infection and cancer escape elimination by host immunity, and it is unknown whether LMP2A can influence the interaction of EBV-infected cells with the immune system. We infected primary B cells with EBV deleted for LMP2A, and established lymphoblastoid cell lines (LCLs). We found that CD8+ T cell clones showed higher reactivity against LMP2A-deficient LCLs compared to LCLs infected with complete EBV. We identified several potential mediators of this immunomodulatory effect. In the absence of LMP2A, expression of some EBV latent antigens was elevated, and cell surface expression of MHC class I was marginally increased. LMP2A-deficient LCLs produced lower amounts of IL-10, although this did not directly affect CD8+ T cell recognition. Deletion of LMP2A led to several changes in the cell surface immunophenotype of LCLs. Specifically, the agonistic NKG2D ligands MICA and ULBP4 were increased. Blocking experiments showed that NKG2D activation contributed to LCL recognition by CD8+ T cell clones. Our results demonstrate that LMP2A reduces the reactivity of CD8+ T cells against EBV-infected cells, and we identify several relevant mechanisms.
Highlights
Epstein-Barr virus (EBV), which belongs to the human herpesvirus family, is a persistent virus carried by more than 90% of the adult population worldwide
How does the virus counteract CD8+ T cell control? Here we study the effects of latent membrane protein 2A (LMP2A), which is an important viral molecule because it is present in several types of EBV-associated cancers, and in latently infected cells in healthy people
EBV infection is under control of a diverse repertoire of antigen-specific T cells, and an important role is played by CD8+ T cells that recognize viral protein-derived peptides presented by MHC class I molecules [2]
Summary
Epstein-Barr virus (EBV), which belongs to the human herpesvirus family, is a persistent virus carried by more than 90% of the adult population worldwide. EBV has a preferential B cell tropism, and latently infected B cells constitute the viral reservoir in healthy carriers [1]. EBV infection is under control of a diverse repertoire of antigen-specific T cells, and an important role is played by CD8+ T cells that recognize viral protein-derived peptides presented by MHC class I molecules [2]. Immunosuppressed patients who lack EBV-specific T cell responses, such as patients after transplantation, are prone to developing EBV-associated lymphoproliferative disease. This condition can be treated or prevented by transfer of EBV-specific T cells [5,6,7]
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