{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:33:08Z","timestamp":1791214388115,"version":"4.1.0"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2009,9,1]],"date-time":"2009-09-01T00:00:00Z","timestamp":1251763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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-\u03b3. We hypothesized that IL-12 and IL-18 are pivotal for induction of IFN-\u03b3 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-\u03b3 production and cell-mediated immune responses.<\/jats:p>","DOI":"10.4049\/jimmunol.0803985","type":"journal-article","created":{"date-parts":[[2009,8,5]],"date-time":"2009-08-05T21:46:31Z","timestamp":1249508791000},"page":"3324-3331","source":"Crossref","is-referenced-by-count":51,"title":["IL-12p40 and IL-18 Play Pivotal Roles in Orchestrating the Cell-Mediated Immune Response to a Poxvirus Infection"],"prefix":"10.1093","volume":"183","author":[{"given":"Yang","family":"Wang","sequence":"first","affiliation":[{"name":"Immunology Program, John Curtin School of Medical Research, Australian National University , Canberra, ACT,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geeta","family":"Chaudhri","sequence":"additional","affiliation":[{"name":"Immunology Program, John Curtin School of Medical Research, Australian National University , Canberra, ACT,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J","family":"Jackson","sequence":"additional","affiliation":[{"name":"Immunology Program, John Curtin School of Medical Research, Australian National University , Canberra, ACT,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunasegaran","family":"Karupiah","sequence":"additional","affiliation":[{"name":"Immunology Program, John Curtin School of Medical Research, Australian National University , Canberra, ACT,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,9,1]]},"reference":[{"key":"2026012811245204600_R1","first-page":"623","article-title":"IRF family of transcription factors as regulators of host defense.","volume-title":"Annu. Rev. Immunol.","year":"2001"},{"key":"2026012811245204600_R2","first-page":"227","article-title":"How cells respond to interferons.","volume-title":"Annu. Rev. Biochem.","year":"1998"},{"key":"2026012811245204600_R3","first-page":"377","article-title":"Poxviruses and immune evasion.","volume-title":"Annu. Rev. Immunol.","year":"2003"},{"key":"2026012811245204600_R4","first-page":"36","article-title":"Viral mimicry of cytokines, chemokines and their receptors.","volume-title":"Nat. Rev. Immunol.","year":"2003"},{"key":"2026012811245204600_R5","first-page":"133","article-title":"Interleukin-12 and the regulation of innate resistance and adaptive immunity.","volume-title":"Nat. Rev. Immunol.","year":"2003"},{"key":"2026012811245204600_R6","first-page":"715","article-title":"Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.","volume-title":"Immunity","year":"2000"},{"key":"2026012811245204600_R7","first-page":"521","article-title":"New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions.","volume-title":"Nat. Rev. Immunol.","year":"2005"},{"key":"2026012811245204600_R8","first-page":"821","article-title":"IL-17 family cytokines and the expanding diversity of effector T cell lineages.","volume-title":"Annu. Rev. Immunol.","year":"2007"},{"key":"2026012811245204600_R9","first-page":"15","article-title":"Interleukin-18: biological properties and clinical implications.","volume-title":"Eur. Cytokine Netw.","year":"2000"},{"key":"2026012811245204600_R10","first-page":"641","article-title":"The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses.","volume-title":"Immunity","year":"2003"},{"key":"2026012811245204600_R11","first-page":"994","article-title":"Compartmental differences in NK cell responsiveness to IL-12 during lymphocytic choriomeningitis virus infection.","volume-title":"J. Immunol.","year":"2000"},{"key":"2026012811245204600_R12","first-page":"2125","article-title":"A mechanism underlying synergy between IL-12 and IFN-\u03b3-inducing factor in enhanced production of IFN-\u03b3.","volume-title":"J. Immunol.","year":"1997"},{"key":"2026012811245204600_R13","first-page":"3948","article-title":"Interleukin-18 together with interleukin-12 inhibits IgE production by induction of interferon-\u03b3 production from activated B cells.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1997"},{"key":"2026012811245204600_R14","first-page":"3214","article-title":"IL-18, but not IL-12, regulates NK cell activity following intranasal herpes simplex virus type 1 infection.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811245204600_R15","first-page":"368","article-title":"IL-18, but not IL-12, is required for optimal cytokine production by influenza virus-specific CD8+ T cells.","volume-title":"Eur. J. Immunol.","year":"2007"},{"key":"2026012811245204600_R16","first-page":"4825","article-title":"Role of interleukin-12 in primary influenza virus infection.","volume-title":"J. Virol.","year":"1998"},{"key":"2026012811245204600_R17","first-page":"6705","article-title":"Interleukin-12 (IL-12) and IL-18 are important in innate defense against genital herpes simplex virus type 2 infection in mice but are not required for the development of acquired \u03b3 interferon-mediated protective immunity.","volume-title":"J. Virol.","year":"2001"},{"key":"2026012811245204600_R18","first-page":"4040","article-title":"IL-12p40 and IL-18 modulate inflammatory and immune responses to respiratory syncytial virus infection.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811245204600_R19","first-page":"341","article-title":"Mouse-pox; infectious ectromelia of mice: a review.","volume-title":"J. Immunol.","year":"1949"},{"key":"2026012811245204600_R20","first-page":"2645","article-title":"Ectromelia virus: the causative agent of mousepox.","volume-title":"J. Gen. Virol.","year":"2005"},{"key":"2026012811245204600_R21","first-page":"93","article-title":"Immunopathogenesis of poxvirus infections: forecasting the impending storm.","volume-title":"Immunol. Cell Biol.","year":"2007"},{"key":"2026012811245204600_R22","first-page":"9057","article-title":"Polarized type 1 cytokine response and cell-mediated immunity determine genetic resistance to mousepox.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2004"},{"key":"2026012811245204600_R23","first-page":"4214","article-title":"Importance of interferons in recovery from mousepox.","volume-title":"J. Virol.","year":"1993"},{"key":"2026012811245204600_R24","first-page":"119","article-title":"Cytokines and immunity to viral infections.","volume-title":"Immunol. Rev.","year":"1997"},{"key":"2026012811245204600_R25","first-page":"12921","article-title":"Interferon function is not required for recovery from a secondary poxvirus infection.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2005"},{"key":"2026012811245204600_R26","first-page":"8301","article-title":"Different roles for CD4+ and CD8+ T lymphocytes and macrophage subsets in the control of a generalized virus infection.","volume-title":"J. Virol.","year":"1996"},{"key":"2026012811245204600_R27","first-page":"4070","article-title":"Induction of natural killer cell responses by ectromelia virus controls infection.","volume-title":"J. Virol.","year":"2007"},{"key":"2026012811245204600_R28","first-page":"e30","article-title":"A role for NKG2D in NK cell-mediated resistance to poxvirus disease.","volume-title":"PLoS Pathog.","year":"2008"},{"key":"2026012811245204600_R29","first-page":"3346","article-title":"Poxvirus-encoded \u03b3 interferon binding protein dampens the host immune response to infection.","volume-title":"J. Virol.","year":"2007"},{"key":"2026012811245204600_R30","first-page":"105","article-title":"Type 1 and type 2 cytokines in antiviral defense.","volume-title":"Vet. Immunol. Immunopathol.","year":"1998"},{"key":"2026012811245204600_R31","first-page":"471","article-title":"IL-12-deficient mice are defective in IFN-\u03b3 production and type 1 cytokine responses.","volume-title":"Immunity","year":"1996"},{"key":"2026012811245204600_R32","first-page":"383","article-title":"Defective NK cell activity and Th1 response in IL-18-deficient mice.","volume-title":"Immunity","year":"1998"},{"key":"2026012811245204600_R33","first-page":"17","article-title":"T cell receptor antagonist peptides induce positive selection.","volume-title":"Cell","year":"1994"},{"key":"2026012811245204600_R34","first-page":"1205","article-title":"Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox.","volume-title":"J. Virol.","year":"2001"},{"key":"2026012811245204600_R35","first-page":"1","article-title":"A general method for the construction of recombinant vaccinia viruses expressing multiple foreign genes.","volume-title":"Gene","year":"1988"},{"key":"2026012811245204600_R36","first-page":"276","article-title":"gpt-gus fusion gene for selection and marker in recombinant poxviruses.","volume-title":"BioTechniques","year":"1997"},{"key":"2026012811245204600_R37","first-page":"941","article-title":"Role of CD8+ cells in the progression of murine adriamycin nephropathy.","volume-title":"Kidney Int.","year":"2001"},{"key":"2026012811245204600_R38","first-page":"290","article-title":"Elevated natural killer cell responses in mice infected with recombinant vaccinia virus encoding murine IL-2.","volume-title":"J. Immunol.","year":"1990"},{"key":"2026012811245204600_R39","first-page":"95","article-title":"Identification of poxvirus CD8+ T cell determinants to enable rational design and characterization of smallpox vaccines.","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012811245204600_R40","first-page":"131","article-title":"Determination of lymphocyte division by flow cytometry.","volume-title":"J. Immunol. Methods","year":"1994"},{"key":"2026012811245204600_R41","first-page":"1140","article-title":"Growth of ectromelia virus in the liver parenchymal cells of different strains of mouse.","volume-title":"Nature","year":"1964"},{"key":"2026012811245204600_R42","first-page":"329","article-title":"Regulatory T cell lineage specification by the forkhead transcription factor foxp3.","volume-title":"Immunity","year":"2005"},{"key":"2026012811245204600_R43","first-page":"677","article-title":"Th17: an effector CD4 T cell lineage with regulatory T cell ties.","volume-title":"Immunity","year":"2006"},{"key":"2026012811245204600_R44","first-page":"64","article-title":"Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-\u03b3 production by dendritic cells.","volume-title":"J. Immunol.","year":"2000"},{"key":"2026012811245204600_R45","first-page":"1907","article-title":"Role of T-bet in commitment of Th1 cells before IL-12-dependent selection.","volume-title":"Science","year":"2001"},{"key":"2026012811245204600_R46","first-page":"234","article-title":"IL-18 bridges innate and adaptive immunity through IFN-\u03b3 and the CD134 pathway.","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012811245204600_R47","first-page":"2261","article-title":"Interleukin-12 is chemotactic for natural killer cells and stimulates their interaction with vascular endothelium.","volume-title":"Blood","year":"1994"},{"key":"2026012811245204600_R48","first-page":"1084","article-title":"Chemoattraction of human T cells by IL-18.","volume-title":"J. Immunol.","year":"2003"},{"key":"2026012811245204600_R49","first-page":"737","article-title":"A CD4+ T cell subset inhibits antigen-specific T cell responses and prevents colitis.","volume-title":"Nature","year":"1997"},{"key":"2026012811245204600_R50","first-page":"389","article-title":"CD4+CD25+ suppressor T cells: more questions than answers.","volume-title":"Nat. Rev. Immunol.","year":"2002"},{"key":"2026012811245204600_R51","first-page":"425","article-title":"Th1 cells control themselves by producing interleukin-10.","volume-title":"Nat. Rev. Immunol.","year":"2007"},{"key":"2026012811245204600_R52","first-page":"201","article-title":"Poxvirus tropism.","volume-title":"Nat. Rev. Microbiol.","year":"2005"},{"key":"2026012811245204600_R53","first-page":"3246","article-title":"A poxvirus protein that binds to and inactivates IL-18, and inhibits NK cell response.","volume-title":"J. 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