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4-1BB Engagement Costimulates NKT Cell Activation and Exacerbates NKT Cell Ligand-Induced Airway Hyperresponsiveness and Inflammation¹

Dong-Hyeon Kim^*, Woo-Sung Chang^*, Yoon-Sook Lee^*, Kyoo-A Lee^*, Yoon-Keun Kim, Byoung S. Kwon and Chang-Yuil Kang^2,*

^* Laboratory of Immunology and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Division of Molecular and Life Science, Department of Life Science, Postech Biotech Center, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea; and Immunomodulation Research Center and Department of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea

Multiple studies have demonstrated that 4-1BB (CD137), a member of the TNF receptor superfamily, is expressed on several immune cells including activated T cells. However, the expression and the role of 4-1BB on natural killer T (NKT) cells have not been fully characterized. In this study, it was shown that 4-1BB was not expressed on naive NKT cells but was rapidly induced on activated NKT cells by TCR engagement with -galactosylceramide (-GalCer). Also, 4-1BB signaling provided by 3H3, an agonistic anti-4-1BB mAb, promoted NKT cell activation resulting in enhanced cytokine production of NKT cells driven by -GalCer. When NKT cell-driven airway immune responses were evaluated by intranasal administration of -GalCer, airway hyperresponsiveness (AHR) and lung inflammation were significantly more aggravated in mice treated with 3H3 and -GalCer than in mice treated with -GalCer alone. These aggravations were accompanied by up-regulation of IL-4, IL-13, and IFN- production. Interestingly, AHR was not developed in IL-4R-deficient mice treated with -GalCer with or without 3H3 but was exacerbated in IFN--deficient mice. Our study suggests that 4-1BB on NKT cells functions as a costimulatory molecule and exacerbates the induction of NKT cell-mediated AHR, which is dependent on the IL-4R-mediated pathway.

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 Korea Research Foundation Grant from the Korean Government (Ministry of Education and Human Resource Development) (KRF-2006-312-E00093).

² Address correspondence and reprint requests to Dr. Chang-Yuil Kang, Laboratory of Immunology and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shillim-9-dong, Kwanak-gu, Seoul 151-742, Republic of Korea. E-mail address: cykang{at}snu.ac.kr

³ Abbreviations used in this paper: NKT, natural killer T; AHR, airway hyperresponsiveness; -GalCer, -galactosylceramide; BAL, bronchoalveolar lavage; BALF, BAL fluid.

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