Impairment of natural killer cytotoxic activity and interferon gamma production in CCAAT/enhancer binding protein gamma-deficient mice

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(-/-)) m ice showed a high mortality rate within 48 h after birth. To analyze the ro les of C/EBP gamma in lymphoid lineage cells, bone marrow chimeras were est ablished. C/EBP gamma(-/-) chimeras showed normal T and B cell development. However, cytolytic functions of their splenic natural killer (NK) cells af ter stimulation with cytokines such as interleukin (IL)-12, IL-18, and IL-2 were significantly reduced as compared with those of control chimera NK ce lls. In addition, the ability of C/EBP gamma(-/-) chimera splenocytes to pr oduce 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(-/-) newborn spleen ce lls. However, they also showed lower cytotoxic activity and IFN-gamma produ ction when stimulated with IL-12 plus IL-18 than control NK cells, as obser ved in C/EBP gamma(-/-) chimera splenocytes. In conclusion, our study revea ls that C/EBP gamma is a critical transcription factor involved in the func tional maturation of NK cells.