Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity.
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.
Maekawa
Yoichi
Y
Department of Immunology & Parasitology, Tokushima, Japan.
Minato
Yoshiaki
Y
Ishifune
Chieko
C
Kurihara
Takeshi
T
Kitamura
Akiko
A
Kojima
Hidefumi
H
Yagita
Hideo
H
Sakata-Yanagimoto
Mamiko
M
Saito
Toshiki
T
Taniuchi
Ichiro
I
Chiba
Shigeru
S
Sone
Saburo
S
Yasutomo
Koji
K
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D053804:Granzymes / Q000235:genetics; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D051883:Receptor, Notch2 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology; D050880:p300-CBP Transcription Factors / Q000276:immunology / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497765:Notch2 protein, mouse; C497571:Rbpj protein, mouse; D051883:Receptor, Notch2; D050880:p300-CBP Transcription Factors; D053804:Granzymes