PARTICIPATION OF ENDOGENOUS TUMOR-NECROSIS-FACTOR-ALPHA IN HOST-RESISTANCE TO CYTOMEGALOVIRUS-INFECTION

Interferon gamma (IFNgamma) represents an essential cytokine involved in murine cytomegalovirus (MCMV) clearance from the salivary gland and the control of horizontal transmission. Because IFNgamma cannot be responsible for all cytokine effects during recovery from MCMV infection we have now tested the potential participation of tumour necrosis factor alpha (TNFalpha) in the antiviral defence. Neutralization of endogenous TNFalpha abolished the antiviral activity of CD4 T cells in immunocompetent as well as in CD8 subset-deficient mice. These data suggest that the antiviral effect of the CD4 subset requires the presence of at least two cytokines, namely IFNgamma and TNFalpha. Depletion of endogenous TNFalpha in adoptive cell transfer recipients diminished the antiviral function of CD8 T lymphocytes suggesting that TNFalpha also participates in CD8 T cell effector functions. Furthermore. endogenous cytokines were found to be required for survival after infection with lethal doses of MCMV, whereas immunotherapy with recombinant TNFalpha. and IFNgamma could not limit virus replication in vivo. The results suggest that, similar to IFNgamma, TNFalpha is an integral part of the protective mechanisms involved in cytomegalovirus clearance.