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.
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We thank T. Kitamura (Tokyo University), S. Reiner (University of Pennsylvania) and J. Fujisawa (Kansai Medical University) for reagents; R. Germain (US National Institutes of Health) for the DCEK cell line and for discussions; K. Ikuta for critical review of the manuscript; C. Kinouchi for technical assistance; and K. Yamakawa for secretarial assistance. Supported by the Japan Society for the Promotion of Science (Grant-in-Aid for Young Scientists (S)), The Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research on Priority Areas), the Takeda Science Foundation, the Sumitomo Foundation and the Mochida Memorial Foundation.
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Maekawa, Y., Minato, Y., Ishifune, C. et al. Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. Nat Immunol 9, 1140–1147 (2008). https://doi.org/10.1038/ni.1649
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