title: Differential regulation of antigen-specific CD8+ T cell responses by IL-12p40 in a dose-dependent manner.
abstract: IL-12p40 is a natural antagonist which inhibits IL-12- and IL-23-mediated biological activity by blocking the binding of IL-12/23 to their receptors. Recently, IL-12p40 was also shown to have immune-enhancing activity through the activation of macrophages or dendritic cells. In this study, we investigated the effects of IL-12p40 as a genetic adjuvant on immune modulation using recombinant adenoviruses expressing IL-12p40 (rAd/IL-12p40) and OVA (rAd/OVA). Coimmunization of rAd/IL-12p40 at a low dose (1 x 10(4) PFU) with rAd/OVA resulted in OVA-specific immune enhancement, while a high dose of rAd/IL-12p40 (1 x 10(8) PFU) caused significant suppression of CD8(+) T cell responses. In addition, the enhancement and suppression of OVA-specific CD8(+) T cell responses correlated with antitumor activity against E.G7-OVA tumor challenge, which subsequently affected the survival rate. Moreover, the differential CD8(+) T cell response by IL-12p40 was still observed in IL-12Rbeta2 knockout (IL-12Rbeta2KO), but not in IL-12Rbeta1 knockout (IL-12Rbeta1KO) mice, indicating that IL-12p40 is a cytokine which can modulate Ag-specific T cell responses depending on IL-12Rbeta1. Our findings provide a novel insight on the physiological role of IL-12p40, which can be informative in the design of vaccine strategies and therapeutic regimens.
authors.affiliation: Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Doo-Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Je-In
authors.initials: JI
authors.lastname: Youn
authors.forename: Sang-Hwan
authors.initials: SH
authors.lastname: Seo
authors.forename: Hyun-Tak
authors.initials: HT
authors.lastname: Jin
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Sung
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology; D009569:Nitric Oxide / Q000097:blood; D010047:Ovalbumin / Q000276:immunology; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D053762:Interleukin-12 Subunit p40; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D010047:Ovalbumin