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Nature Immunology 9, 1140–1147 (1 October 2008) | doi:10.1038/ni.1649

Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity

Yoichi Maekawa , Yoshiaki Minato , Chieko Ishifune , Takeshi Kurihara , Akiko Kitamura , Hidefumi Kojima , Hideo Yagita , Mamiko Sakata-Yanagimoto , Toshiki Saito , Ichiro Taniuchi , Shigeru Chiba , Saburo Sone & Koji Yasutomo

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.