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IL-12p40 and IL-18 Play Pivotal Roles in Orchestrating the Cell-Mediated Immune Response to a Poxvirus Infection¹

Immunology Program, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

A strong cell-mediated immune response is critical for controlling viral infections and is regulated by a number of cytokines, including IL-12 and IL-18. Indeed, some viruses have evolved to specifically target these pathways to counter the host immune response. Orthopoxviruses, including ectromelia virus, encode immune evasion molecules that specifically target IL-18 and IFN-. We hypothesized that IL-12 and IL-18 are pivotal for induction of IFN- production and subsequent generation of an effective host response to ectromelia virus infection. In this study, we demonstrate that absence of both IL-12p40 and IL-18 resulted in increased susceptibility to infection that was associated with skewing of the cytokine response to Th2 and a reduction in NK and CTL responses. The decrease in CTL response correlated with a defect in CD8⁺ T cell proliferation and lower numbers of virus-specific CD8⁺ T cells. Lack of either IL-12p40 and/or IL-18 was also associated with reduced numbers of CD8⁺ T cells at sites of infection and with an increase in the numbers of splenic T regulatory cells. Taken together, our data indicate that IL-12p40 and IL-18 act in concert and play an important antiviral role through the up-regulation of IFN- production and cell-mediated immune responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by project grants to G.K. and G.C. from National Health and Medical Research Council (NHMRC) of Australia, an International Research Scholars Special Initiative grant on infectious diseases to G.K. from the Howard Hughes Medical Institute, a senior research fellowship (NHMRC) to G.K., and a C. J. Martin Fellowship (NHMRC) to Y.W.

² Address correspondence and reprint requests to Dr. Gunasegaran Karupiah, Immunology Program, John Curtin School of Medical Research, Australian National University, P.O. Box 334, Canberra ACT 2601, Australia. E-mail address: Guna.Karupiah{at}anu.edu.au

³ Abbreviations used in this paper: ECTV, ectromelia virus; DC, dendritic cell; ECTV-OVA, ECTV encoding OVA; IHC, immunohistochemistry; LN, lymph node; p.i., postinfection; Treg, regulatory T; WT, wild type.

⁴ The online version of this article contains supplemental material.

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