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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- (TNF-) Receptor-1 and Confers Resistance to TNF--Induced Apoptosis in T Cells

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

Huai-Chia Chuang^*, Jong-Ding Lay, Shuang-En Chuang, Wen-Chuan Hsieh^*, Yao Chang^* and Ih-Jen Su^*¶

From the Divisions of Clinical Research^* and Cancer Research, National Health Research Institutes, Taipei; the Department of Nursing, National Taichung Nursing College, Taichung; and the Graduate Institutes of Basic Medicine 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- (TNF-), 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-. LMP-1 up-regulated TNF- through TRAF2,5 and nuclear factor-B pathway in T cells. The LMP-1-expressing T cells then became resistant to TNF--induced apoptosis. Interestingly, the expression of TNFR1 was remarkably down-regulated by LMP-1 in T cells. Furthermore, the TNF-/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--induced apoptotic cascades. Therefore, EBV LMP-1 not only activates T cells to proliferate but also confers resistance to TNF--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.