Article abstract
Nature Immunology 9, 1140 - 1147 (2008)
Published online: 24 August 2008 | doi:10.1038/ni.1649
Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity
Yoichi Maekawa1,8, Yoshiaki Minato1,2,8, Chieko Ishifune1, Takeshi Kurihara1, Akiko Kitamura1, Hidefumi Kojima3, Hideo Yagita4, Mamiko Sakata-Yanagimoto5,6, Toshiki Saito5, Ichiro Taniuchi7, Shigeru Chiba5,6, Saburo Sone2 & Koji Yasutomo1
Abstract
The acquisition of cytotoxic effector function by CD8+ T cells is crucial for the control of intracellular infection and tumor invasion. However, it remains unclear which signaling pathways are required for the differentiation of CD8+ cytotoxic T lymphocytes. We show here that Notch2-deficient T cells had impaired differentiation into cytotoxic T lymphocytes. In addition, dendritic cells with lower expression of the Notch ligand Delta-like 1 induced the differentiation of cytotoxic T lymphocytes less efficiently. We found that the intracellular domain of Notch2 interacted with a phosphorylated form of the transcription factor CREB1, and together these proteins bound the transcriptional coactivator p300 to form a complex on the promoter of the gene encoding granzyme B. Our results suggest that the highly regulated, dynamic control of T cell cytotoxicity depends on the integration of Notch2 and CREB1 signals.
- Department of Immunology & Parasitology, Tokushima 770-8503, Japan.
- Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
- Department of Immunology, Dokkyo Medical University, Tochigi 321-0293, Japan.
- Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
- Department of Cell Therapy and Transplantation Medicine, University of Tokyo, Tokyo 113-8655, Japan.
- Department of Clinical and Experimental Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
- Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan.
- These authors contributed equally to this work.
Correspondence to: Koji Yasutomo1 e-mail: yasutomo@basic.med.tokushima-u.ac.jp
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