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

Nature Immunology volume 9, pages 1140–1147 (2008)Cite this article

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.

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Figure 1: Notch signals control cytotoxic T cell differentiation in vitro and in vivo.
Figure 2: Notch2 on CD8+ T cells promotes CTL induction in vitro and in vivo.
Figure 3: Notch2 signaling induces the transcription of genes encoding CTL effector molecules independently of Eomes.
Figure 4: Notch2 directly regulates Gzmb transcription.
Figure 5: CREB1 is required for Notch2-mediated granzyme B expression through interaction of the intracellular domain of Notch2 with pCREB1.
Figure 6: Notch2 interacts with pCREB1 and stably recruits p300 to the Gzmb promoter.

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Acknowledgements

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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Author notes

  1. Yoichi Maekawa and Yoshiaki Minato: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology & Parasitology, Tokushima, 770-8503, Japan

    Yoichi Maekawa, Yoshiaki Minato, Chieko Ishifune, Takeshi Kurihara, Akiko Kitamura & Koji Yasutomo

  2. Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 770-8503, Japan

    Yoshiaki Minato & Saburo Sone

  3. Department of Immunology, Dokkyo Medical University, Tochigi, 321-0293, Japan

    Hidefumi Kojima

  4. Department of Immunology, Juntendo University School of Medicine, Tokyo, 113-8421, Japan

    Hideo Yagita

  5. Department of Cell Therapy and Transplantation Medicine, University of Tokyo, Tokyo, 113-8655, Japan

    Mamiko Sakata-Yanagimoto, Toshiki Saito & Shigeru Chiba

  6. Department of Clinical and Experimental Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8575, Japan

    Mamiko Sakata-Yanagimoto & Shigeru Chiba

  7. Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, 230-0045, Japan

    Ichiro Taniuchi

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Contributions

Y.Ma., Y.Mi., C.I., T.K., A.K. and H.K. did research and analyzed data; H.Y. established antibodies; M.S.-Y., T.S., I.T., and S.C. established genes modified mice; S.S. provided advice for the experiments; and Y.Ma. and K.Y. designed research and wrote the paper.

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Correspondence to Koji Yasutomo.

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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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