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The Journal of Immunology, 1998, 160: 3958-3964.
Copyright © 1998 by The American Association of Immunologists

Mice Lacking IL-12 Develop Polarized Th1 Cells During Viral Infection

Virgil E. C. J. Schijns1,*, Bart L. Haagmans*, Christel M. H. Wierda*, Boudewijn Kruithof*, Ingmar A. F. M. Heijnen{dagger}, Gottfried Alber{ddagger} and Marian C. Horzinek*

* Virology Unit, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands; {dagger} Department of Immunology, University Hospital Utrecht, Utrecht, The Netherlands; and {ddagger} Immunology Unit, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany

Studies in IL-12-deficient mice established the necessity for IL-12 to generate a Th1 cytokine response that is often required for elimination of intracellular pathogens. In this study, we demonstrate that mice with a targeted disruption of the IL-12p40 and/or p35 gene effectively control liver damage induced by mouse hepatitis virus (MHV) infection, similar to wild-type animals. In contrast, MHV-infected IFN-{gamma} receptor-deficient (IFN-{gamma}R-/-) mice showed an increased susceptibility to coronaviral hepatitis. Surprisingly, MHV-infected mice lacking IL-12 produced a polarized Th1-type cytokine response, as evidenced by high IFN-{gamma} and nondetectable IL-4 production by CD4+ splenocytes and normal virus-specific serum IgG2a/IgG1 ratios. The virus-induced type 1 cytokine secretion pattern was not reversed in IL-12-deficient mice by in vivo neutralization of IFN-{gamma} nor in IFN-{gamma}R-/- mice receiving IL-12-neutralizing Abs. In IL-12-deficient mice, Th1-type responses were also generated upon immunization with inactivated MHV. In contrast, following immunization with keyhole limpet hemocyanin, mice lacking IL-12 mounted strongly reduced specific IgG2a and increased IgE responses, indicative of a type 2-dominated cytokine pattern. These findings demonstrate that following a virus infection, IL-12 is not essential for the generation of polarized T cell type 1 cytokine expression and associated immune responses, which is in marked contrast to nonviral systems. Our data suggest that viruses may selectively induce IFN-{gamma} production and Th1-type immune reactions even in the absence of IL-12.




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