Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) increases IL-10 via Bruton’s tyrosine kinase and STAT3: Effect on T cell function

Abstract

Abstract Data from our laboratory demonstrate that Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) promotes B cell lymphoma survival by enhancing IL-10 production, which has important implications in the treatment of EBV-associated B cell tumors. To determine the pathway used by LMP2A to increase IL-10, pharmacological inhibitors were added to LMP2A-expressing B cells and IL-10 was assessed. Our findings indicate for the first time, that LMP2A activates BTK to phosphorylate STAT3 in B cell tumors, which mediates the LMP2A-dependent increase in IL-10. Additionally, we assessed whether the LMP2A-mediated increase in IL-10 is immunosuppresssive to cytotoxic T cells that are critical for controlling the growth of EBV-associated tumors. Purified human CD8+ T cells activated with anti-CD3/CD28 mAbs were exposed to supernatants from either LMP2A-negative or –positive B cell lines for 48 hours. Our findings indicate that there is no difference in proliferation and IFN-γ secretion by activated CD8+ T cells exposed to supernatants from LMP2A-positive B cell lymphomas when compared to CD8+ T cells exposed to supernatants from LMP2A-negative B cell lymphomas. Although the LMP2A-mediated increase in IL-10 does not significantly influence the CD8+ T cell response, these findings highlight the possibility of using BTK and STAT3 inhibitors in clinical trials to treat EBV-associated lymphomas that express LMP2A. This work was supported by NIH grant 1R15CA149690-01.