Latent Membrane Protein LMP2A Impairs Recognition of EBV-Infected Cells by CD8+ T Cells

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.

NKG2A-Expressing Natural Killer Cells Dominate the Response to Autologous Lymphoblastoid Cells Infected with Epstein–Barr Virus

“…While Azzi et al (7) reported an increase in MHC class I expression on autologous LCLs compared to CD19 + B cells from PBMCs, it is unclear if they accounted for differences in autofluorescence between the two cell types. In accord with our results, LCLs generated from an EBV strain lacking the latent protein LMP2a display increased MHC class I expression, suggesting that latent viral genes can downregulate MHC class I expression (50). Along similar lines, the downregulation of inhibitory ligands and an upregulation of activating ligands are thought to contribute to the NK response toward lytic EBV.…”

Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 production through the activation of Bruton's tyrosine kinase and STAT3

“…Additionally, it is possible that the LMP2A-mediated increase may also influence the anti-tumor response induced by cytotoxic T cells (CTLs), since IL-10 dampens cell-mediated immunity (Groux et al, 1998; Klinker and Lundy, 2012). A recent study confirms that LMP2A increases IL-10 production, but the change in IL-10 was insufficient to influence CTL activity in their study (Rancan et al, 2015). It is possible that the influence of IL-10 on CTL function may be dependent on the program of EBV latency and the interplay of latency proteins.…”

Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential

“…A number of potential roles for LMP2A in enhancing EBV persistence and/or EBV-associated lymphomas have been proposed, which include regulating the latent-to-lytic switch (45,46), inducing plasma cell differentiation (35), promoting the survival of B cells that have undergone nonproductive BCR rearrangements (21), cooperating with c-Myc overexpression to induce Burkitt-like lymphomas (50,51), and inhibiting the host immune response (52,53). However, many of those previous studies expressed LMP2A at nonphysiological levels and/or were performed outside the context of the intact viral genome.…”