ABSTRACT
Human group C adenoviruses cause an acute infection in respiratory epithelia and establish a long-term or persistent infection, possibly in lymphocytes. The mechanism by which this persistence is maintained is unknown; however, it would require that persistently infected lymphocytes not be deleted. The adenovirus genome encodes proteins that prevent the immune system from eliminating the virus-infected cell, including the E3 receptor internalization and degradation (RID) complex. The RID complex prevents death of infected cells by blocking apoptosis initiated through death domain-containing receptors of the tumor necrosis factor receptor (TNFR) superfamily, including TNFR1 (L. R. Gooding, T. S. Ranheim, A. E. Tollefson, L. Aquino, P. Duerksen-Hughes, T. M. Horton, and W. S. Wold, J. Virol. 65:4114-4123, 1991), TNF-related apoptosis-inducing ligand receptors (TRAIL-R1 and -R2) (C. A. Benedict, P. S. Norris, T. I. Prigozy, J. L. Bodmer, J. A. Mahr, C. T. Garnett, F. Martinon, J. Tschopp, L. R. Gooding, and C. F. Ware, J. Biol. Chem. 276:3270-3278, 2001; A. E. Tollefson, K. Toth, K. Doronin, M. Kuppuswamy, O. A. Doronina, D. L. Lichtenstein, T. W. Hermiston, C. A. Smith, and W. S. Wold, J. Virol. 75:8875-8887, 2001), and Fas (J. Shisler, C. Yang, B. Walter, C. F. Ware, and L. R. Gooding, J. Virol. 71:8299-8306, 1997). Here, we test the ability of RID to protect human lymphocytes from apoptosis induced by ligation of Fas, a mechanism important for regulating lymphocyte populations. Using a retrovirus expressing RID to infect six human lymphocyte cell lines, we found that RID functions in the absence of other viral proteins to downregulate surface Fas on some, but not all, cell lines. Total cellular levels of Fas decrease as measured by Western blotting, and this loss of Fas correlates with protection from apoptosis induced by ligation of Fas in every cell line tested. Although in some cases, RID causes loss of only a fraction of surface Fas, the presence of RID completely blocks the immediate events downstream of Fas ligation (i.e., Fas-FADD association and caspase-8 cleavage) in susceptible cell lines. Nonetheless, the ability of RID to block Fas signaling is independent of the Fas signaling pathway used (type I or type II). Interestingly, among the four T-cell lines tested, RID caused loss of Fas in the two T-cell lines bearing a relatively immature phenotype, while having no activity in T cells with mature phenotypes. Collectively, these data suggest that RID functions to prevent apoptosis of some human lymphocytes by internalizing surface Fas receptors. It is possible that the expression of RID facilitates long-term infection by preventing Fas-mediated deletion of persistently infected lymphocytes.
Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins
