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*
Virology Unit, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands;
Department of Immunology, University Hospital Utrecht, Utrecht, The Netherlands; and
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-
receptor-deficient (IFN-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- 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- nor in IFN-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- production and Th1-type immune reactions
even in the absence of IL-12.
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