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* 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.
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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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