TY - JOUR
T1 - Murine cytomegalovirus infection inhibits IFNγ-induced MHC class ii expression on macrophages. The role of type I interferon
AU - Heise, Mark T.
AU - Pollock, Jessica L.
AU - O'Guin, Andrew
AU - Barkon, Melissa L.
AU - Bromley, Shannon
AU - Virgin IV, Herbert W.
N1 - Funding Information:
This work was supported by Grant AI39616 to H.W.V. from the National Institute of Allergy and Infectious Diseases. Additional support to H.W.V. was provided by a grant to H.W.V. from the Mallinckrodt Foundation, the Council for Tobacco Research, and American Cancer Society Junior Faculty Research Award JFRA-525. M.T.H was supported by National Institute of Health Training Grant ST32 AI07163. We thank Dr. Ion Gresser for generously providing neutralizing antibody against IFNαβ and Genentech, Inc., for providing recombinant murine IFNγ.
PY - 1998/2/15
Y1 - 1998/2/15
N2 - Macrophage (Mφ) activation, as measured by cell surface expression of MHC class II, was examined during infection of immunocompetent and immunocompromised mice with murine cytomegalovirus (MCMV). Intraperitoneal infection of CB17 SOlD mice with 106 PFU of MCMV elicited a large population of Mφ which expressed low levels of MHC class II. This was surprising since infection of SOID mice with lower doses (e.g., 104 PFU) of MCMV elicits Mφ expressing high levels of MHC class II (M. T. Heise and H. W. Virgin, J. Virol. (1995) 69, 904-909). In vivo administration of recombinant mouse IFNγ resulted in high levels of MHC class II expression on Mφ from control but not MCMV-infected SCID mice, suggesting that MCMV infection generates a state in which IFNγ is not effective at activating Mφ. The effect of MCMV infection was MHC Class II specific, since MHC Class I and ICAM-1 levels were increased on Mφ expressing low levels of MHC class II. Interference with IFNγ action was not due to productive or abortive infection of Mφ. This suggested that MCMV infection induces a soluble factor that alters Mφ responsiveness to IFNγ. Infection of SOlD mice with 106 PFU of MCMV induced higher levels of serum IFNαβ (one candidate for inhibition of IFNγ induction of MHC class II expression) than infection with 104 PFU. We therefore evaluated the role of MCMV-induced IFNαβ on IFNγ responses of bone marrow-derived (BMMφ) or thioglycollate-elicited Mφ in vitro. Infection of normal Mφ with MCMV at a low m.o.i. (0.1 to 0.2) impaired IFNγ-mediated induction of Mφ MHC class II expression, but not MHC class I expression. Inhibition of IFNγ responses was not observed in Mφ from mice with a null mutation in the IFNαβ receptor (IFNαβR-/-). To test the in vivo relevance of virus-induced IFNαβ to IFNγ-mediated responses, the kinetics of MHC class II induction during MCMV infection of IFNαβR-/- mice was evaluated. MCMV-infected IFNαβR-/- mice mounted an earlier Mφ MHC class II response than normal mice. We conclude that MCMV infection specifically impairs IFNγ-mediated MHC class II expression on Mφ and that induction of IFNαβ is one mechanism by which this inhibition occurs.
AB - Macrophage (Mφ) activation, as measured by cell surface expression of MHC class II, was examined during infection of immunocompetent and immunocompromised mice with murine cytomegalovirus (MCMV). Intraperitoneal infection of CB17 SOlD mice with 106 PFU of MCMV elicited a large population of Mφ which expressed low levels of MHC class II. This was surprising since infection of SOID mice with lower doses (e.g., 104 PFU) of MCMV elicits Mφ expressing high levels of MHC class II (M. T. Heise and H. W. Virgin, J. Virol. (1995) 69, 904-909). In vivo administration of recombinant mouse IFNγ resulted in high levels of MHC class II expression on Mφ from control but not MCMV-infected SCID mice, suggesting that MCMV infection generates a state in which IFNγ is not effective at activating Mφ. The effect of MCMV infection was MHC Class II specific, since MHC Class I and ICAM-1 levels were increased on Mφ expressing low levels of MHC class II. Interference with IFNγ action was not due to productive or abortive infection of Mφ. This suggested that MCMV infection induces a soluble factor that alters Mφ responsiveness to IFNγ. Infection of SOlD mice with 106 PFU of MCMV induced higher levels of serum IFNαβ (one candidate for inhibition of IFNγ induction of MHC class II expression) than infection with 104 PFU. We therefore evaluated the role of MCMV-induced IFNαβ on IFNγ responses of bone marrow-derived (BMMφ) or thioglycollate-elicited Mφ in vitro. Infection of normal Mφ with MCMV at a low m.o.i. (0.1 to 0.2) impaired IFNγ-mediated induction of Mφ MHC class II expression, but not MHC class I expression. Inhibition of IFNγ responses was not observed in Mφ from mice with a null mutation in the IFNαβ receptor (IFNαβR-/-). To test the in vivo relevance of virus-induced IFNαβ to IFNγ-mediated responses, the kinetics of MHC class II induction during MCMV infection of IFNαβR-/- mice was evaluated. MCMV-infected IFNαβR-/- mice mounted an earlier Mφ MHC class II response than normal mice. We conclude that MCMV infection specifically impairs IFNγ-mediated MHC class II expression on Mφ and that induction of IFNαβ is one mechanism by which this inhibition occurs.
UR - http://www.scopus.com/inward/record.url?scp=0032520145&partnerID=8YFLogxK
U2 - 10.1006/viro.1997.8969
DO - 10.1006/viro.1997.8969
M3 - Article
C2 - 9499808
AN - SCOPUS:0032520145
VL - 241
SP - 331
EP - 344
JO - Virology
JF - Virology
SN - 0042-6822
IS - 2
ER -