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



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.
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