The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/12/1573/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 11, December 6, 1999 1573-1582

Original Article

Impairment of Natural Killer Cytotoxic Activity and Interferon {gamma} Production in CCAAT/Enhancer Binding Protein {gamma}–deficient Mice

Tsuneyasu Kaishoa,d, Hiroko Tsutsuib,d, Takashi Tanakae, Tohru Tsujimurac, Kiyoshi Takedad,f, Taro Kawaid,f, Nobuaki Yoshidag, Kenji Nakanishia,b,d, and Shizuo Akirad,f
a Institute for Advanced Medical Sciences, Hyogo College of Medicine, Hyogo 663-8501, Japan
b Department of Immunology and Medical Zoology, Hyogo College of Medicine, Hyogo 663-8501, Japan
c Department of Pathology, Hyogo College of Medicine, Hyogo 663-8501, Japan
d Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation, Tokyo 101-0062, Japan
e Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115
f Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
g Division of Gene Expression and Regulation, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Correspondence to: Shizuo Akira, Dept. of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Tel:81-6-6879-8302 Fax:81-6-6879-8305 E-mail:sakira{at}biken.osaka-u.ac.jp.

We have investigated in vivo roles of CCAAT/enhancer binding protein {gamma} (C/EBP{gamma}) by gene targeting. C/EBP{gamma}-deficient (C/EBP{gamma}2/-) mice showed a high mortality rate within 48 h after birth. To analyze the roles of C/EBP{gamma} in lymphoid lineage cells, bone marrow chimeras were established. C/EBP{gamma}2/- chimeras showed normal T and B cell development. However, cytolytic functions of their splenic natural killer (NK) cells after stimulation with cytokines such as interleukin (IL)-12, IL-18, and IL-2 were significantly reduced as compared with those of control chimera NK cells. In addition, the ability of C/EBP{gamma}-/- chimera splenocytes to produce interferon (IFN)-{gamma} in response to IL-12 and/or IL-18 was markedly impaired. NK cells could be generated in vitro with normal surface marker expression in the presence of IL-15 from C/EBP{gamma}2/- newborn spleen cells. However, they also showed lower cytotoxic activity and IFN-{gamma} production when stimulated with IL-12 plus IL-18 than control NK cells, as observed in C/EBP{gamma}2/- chimera splenocytes. In conclusion, our study reveals that C/EBP{gamma} is a critical transcription factor involved in the functional maturation of NK cells.

Key Words: gene targeting, natural killer cells, C/EBP{gamma}, interleukin 15, interferon {gamma}


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