IL-4 and IL-10 antagonize IL-12-mediated protection against acute vaccinia virus infection with a limited role of IFN-gamma and nitric oxide synthetase 2.
Resistance or susceptibility to most infectious diseases is strongly determined by the balance of type 1 vs type 2 cytokines produced during infection. However, for viruses, this scheme may be applicable only to infections with some cytopathic viruses, where IFN-gamma is considered as mandatory for host defense with little if any participation of type 2 responses. We studied the role of signature Th1 (IL-12, IFN-gamma) and Th2 (IL-4, IL-10) cytokines for immune responses against vaccinia virus (VV). IL-12-/- mice were far more susceptible than IFN-gamma-/- mice, and primary CTL responses against VV were absent in IL-12-/- mice but remained intact in IFN-gamma-/- mice. Both CD4+ and CD8+ T cells from IL-12-/- mice were unimpaired in IFN-gamma production, although CD4+ T cells showed elevated Th2 cytokine responses. Virus replication was impaired in IL-4-/- mice and, even more strikingly, in IL-10-/- mice, which both produced elevated levels of the proinflammatory cytokines IL-1alpha and IL-6. Thus, IL-4 produced by Th2 cells and IL-10 produced by Th2 cells and probably also by macrophages counteract efficient anti-viral host defense. Surprisingly, NO production, which is considered as a major type 1 effector pathway inhibited by type 2 cytokines, appears to play a limited role against VV, because NO sythetase 2-deficient mice did not show increased viral replication. Thus, our results identify a new role for IL-12 in defense beyond the induction of IFN-gamma and show that IL-4 and IL-10 modulate host protective responses to VV.
van Den Broek
M
M
Institute for Experimental Immunology, Zürich, Switzerland.
Bachmann
M F
MF
Köhler
G
G
Barner
M
M
Escher
R
R
Zinkernagel
R
R
Kopf
M
M
D000208:Acute Disease; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004198:Disease Susceptibility; D005260:Female; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016753:Interleukin-10 / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D011994:Recombinant Proteins / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014615:Vaccinia / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014779:Virus Replication
D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse