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Differential Regulation of Antigen-Specific CD8⁺ T Cell Responses by IL-12p40 in a Dose-Dependent Manner¹

Doo-Jin Kim^*, Je-In Youn^*, Sang-Hwan Seo^*, Hyun-Tak Jin and Young-Chul Sung^2,*,

^* Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang; and Research Institute, Genexine Co. Ltd., Seoul, Republic of Korea

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 10⁴ PFU) with rAd/OVA resulted in OVA-specific immune enhancement, while a high dose of rAd/IL-12p40 (1 x 10⁸ 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-12Rβ2 knockout (IL-12Rβ2KO), but not in IL-12Rβ1 knockout (IL-12Rβ1KO) mice, indicating that IL-12p40 is a cytokine which can modulate Ag-specific T cell responses depending on IL-12Rβ1. 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.

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 a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A020598), supported by a grant from Science Research Center fund to Immunomodulation Research Center at University of Ulsan from the Korea Science and Engineering Foundation and the Korea Ministry of Science and Technology, supported by Growth Engine Technology Development Program by the Ministry of Commerce, Industry and Energy (10028480-2006-11), and supported by Generic Technology Development Program, Minister of Commerce, Industry and Energy (10020817).

² Address correspondence and reprint requests to Dr. Young-Chul Sung, Division of Molecular and Life Sciences, Pohang University of Science and Technology, San 31 Hyoja-dong, Pohang 790-784, Republic of Korea. E-mail address: ycsung{at}postech.ac.kr

³ Abbreviations used in this paper: DC, dendritic cell; Mtb, Mycobacterium tuberculosis; rAd, recombinant adenovirus; EGFP, enhanced GFP; KO, knockout.

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