MURINE CYTOMEGALOVIRUS-INFECTION INHIBITS IFN-GAMMA-INDUCED MHC CLASS-II EXPRESSION ON MACROPHAGES - THE ROLE OF TYPE-I INTERFERON

Macrophage (M phi) activation, as measured by cell surface expression of MHC class II, was examined during infection of immunocompetent and immunocompromised mice with murine cytomegalovirus (MCMV). Intraperito neal infection of CB17 SCID mice with 10(8) PFU of MCMV elicited a lar ge population of M phi which expressed low revels of MHC class II. Thi s was surprising since infection of SCID mice with lower doses (e.g., 10(4) PFU) of MCMV elicits M phi expressing high levels of MHC class I I (M. T. Heise and H. W. Virgin, J. Virol. (1995) 69, 904-909). In viv o administration of recombinant mouse IFN gamma resulted in high level s of MHC class II expression on M phi from control but not MGMV-infect ed SCID mice, suggesting that MCMV infection generates a state in whic h IFN gamma is not effective at activating M phi. The effect of MCMV i nfection was MHC class II specific, since MHC class I and ICAM-1 level s were increased on M phi expressing low levels of MHC class II. Inter ference with IFN gamma action was not due to productive or abortive in fection of M phi. This suggested that MCMV infection induces a soluble factor that alters M phi responsiveness to IFN gamma. Infection of SC ID mice with 10(6) PFU of MCMV induced higher revels of serum IFN alph a beta (one candidate for inhibition of IFN gamma induction of MHC cla ss II expression) then infection with 10(4) PFU. We therefore evaluate d the role of MCMV-induced IFN alpha beta on IFN gamma responses of bo ne marrow-derived (BMM phi) or thioglycollate-elicited M phi in vitro. Infection of normal M phi with MCMV at a low m.o.i. (0.1 to 0.2) impa ired IFN gamma-mediated induction of M phi MHC class II expression, bu t not MHC class I expression. inhibition of IFN gamma responses was no t observed in M phi from mice with a null mutation in the IFN alpha be ta receptor (IFN alpha beta R-/-). To test the in vivo relevance of vi rus-induced IFN alpha beta to IFN gamma-mediated responses, the kineti cs of MHC class II induction during MCMV infection of IFN alpha beta R -/-mice was evaluated. MCMV-infected IFN alpha beta R-/-mice mounted a n earlier M phi MHC class II response than normal mice. We conclude th at MCMV infection specifically impairs IFN gamma-mediated MHC class II expression on M phi and that induction of IFN alpha beta is one mecha nism by which this inhibition occurs. (C) 1998 Academic Press.