Mice lacking IL-12 develop polarized Th1 cells during viral infection.
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-gammaR[-/-]) 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-gammaR(-/-) 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.
Schijns
V E
VE
Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands. virgil.schijns@intervet.akzonobel.nl
Haagmans
B L
BL
Wierda
C M
CM
Kruithof
B
B
Heijnen
I A
IA
Alber
G
G
Horzinek
M C
MC
D000818:Animals; D018352:Coronavirus Infections / Q000209:etiology / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D009500:Neutralization Tests; D018417:Th1 Cells / Q000276:immunology*; D014779:Virus Replication
D007074:Immunoglobulin G; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma