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(American Journal of Pathology. 2007;170:1607-1617.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061026

Epstein-Barr Virus (EBV) Latent Membrane Protein-1 Down-Regulates Tumor Necrosis Factor-{alpha} (TNF-{alpha}) Receptor-1 and Confers Resistance to TNF-{alpha}-Induced Apoptosis in T Cells

Implication for the Progression to T-Cell Lymphoma in EBV-Associated Hemophagocytic Syndrome

Huai-Chia Chuang*{dagger}, Jong-Ding Lay{ddagger}§, Shuang-En Chuang{ddagger}, Wen-Chuan Hsieh*, Yao Chang* and Ih-Jen Su*¶

From the Divisions of Clinical Research* and Cancer Research,{ddagger} National Health Research Institutes, Taipei; the Department of Nursing,§ National Taichung Nursing College, Taichung; and the Graduate Institutes of Basic Medicine{dagger} and Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan

The infection of T cells by Epstein-Barr virus (EBV) may result in hemophagocytic syndrome (HPS) through enhanced cytokine secretion, particularly tumor necrosis factor-{alpha} (TNF-{alpha}), by EBV latent membrane protein-1 (LMP-1). One bewildering observation of HPS patients is relapsing disease or progression to T-cell lymphoma. This finding raises the question whether EBV LMP-1-expressing T cells may survive and proliferate in the cytokine milieu of HPS. To explore this possibility, we tested the sensitivity of LMP-1-expressing T cells to apoptosis in the presence of TNF-{alpha}. LMP-1 up-regulated TNF-{alpha} through TRAF2,5 and nuclear factor-{kappa}B pathway in T cells. The LMP-1-expressing T cells then became resistant to TNF-{alpha}-induced apoptosis. Interestingly, the expression of TNFR1 was remarkably down-regulated by LMP-1 in T cells. Furthermore, the TNF-{alpha}/TNFR1 downstream death signal TNFR1-associated death domain protein was constitutively recruited by LMP-1, and the activities of apoptotic caspases 3, 8, and 9 were suppressed. Reconstitution of TNFR1 successfully reversed the TNF-{alpha}-induced apoptotic cascades. Therefore, EBV LMP-1 not only activates T cells to proliferate but also confers resistance to TNF-{alpha}-mediated apoptosis via down-regulation of TNFR1 in the cytokine milieu of HPS. This finding provides a potential mechanism to explain the disease persistence or progression to T-cell lymphoma in HPS patients.




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H.-C. Chuang, J.-M. Wang, W.-C. Hsieh, Y. Chang, and I.-J. Su
Up-Regulation of Activating Transcription Factor-5 Suppresses SAP Expression to Activate T Cells in Hemophagocytic Syndrome Associated with Epstein-Barr Virus Infection and Immune Disorders
Am. J. Pathol., November 1, 2008; 173(5): 1397 - 1405.
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