title: A central role for Notch in effector CD8(+) T cell differentiation.
abstract: Activated CD8(+) T cells choose between terminal effector cell (TEC) or memory precursor cell (MPC) fates. We found that the signaling receptor Notch controls this 'choice'. Notch promoted the differentiation of immediately protective TECs and was correspondingly required for the clearance of acute infection with influenza virus. Notch activated a major portion of the TEC-specific gene-expression program and suppressed the MPC-specific program. Expression of Notch was induced on naive CD8(+) T cells by inflammatory mediators and interleukin 2 (IL-2) via pathways dependent on the metabolic checkpoint kinase mTOR and the transcription factor T-bet. These pathways were subsequently amplified downstream of Notch, creating a positive feedback loop. Notch thus functions as a central hub where information from different sources converges to match effector T cell differentiation to the demands of an infection.
authors.affiliation: 1] Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, the Netherlands. [2] Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Backer
authors.affiliation: 1] Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, the Netherlands. [2] Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
authors.forename: Christina
authors.initials: C
authors.lastname: Helbig
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gentek
authors.affiliation: The Icahn School of Medicine at Mount Sinai, Immunology Institute and Tisch Cancer Institute, Department of Medicine, New York, New York, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kent
authors.affiliation: Department of Immunobiology and Howard Hughes Medical Institute, Yale University, School of Medicine, New Haven, Connecticut, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Laidlaw
authors.affiliation: Department of Immunobiology and Howard Hughes Medical Institute, Yale University, School of Medicine, New Haven, Connecticut, USA.
authors.forename: Claudia X
authors.initials: CX
authors.lastname: Dominguez
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Yevan S
authors.initials: YS
authors.lastname: de Souza
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands; Viroclinics Biosciences BV, Rotterdam, the Netherlands.
authors.forename: Stella E
authors.initials: SE
authors.lastname: van Trierum
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands; Viroclinics Biosciences BV, Rotterdam, the Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: van Beek
authors.affiliation: Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands; Viroclinics Biosciences BV, Rotterdam, the Netherlands.
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.affiliation: Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: ten Brinke
authors.affiliation: Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: A Marcel
authors.initials: AM
authors.lastname: Willemsen
authors.affiliation: Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Antoine H C
authors.initials: AH
authors.lastname: van Kampen
authors.affiliation: Department of Immunobiology and Howard Hughes Medical Institute, Yale University, School of Medicine, New Haven, Connecticut, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.affiliation: The Icahn School of Medicine at Mount Sinai, Immunology Institute and Tisch Cancer Institute, Department of Medicine, New York, New York, USA.
authors.forename: J Magarian
authors.initials: JM
authors.lastname: Blander
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
authors.forename: Klaas
authors.initials: K
authors.lastname: van Gisbergen
authors.affiliation: 1] Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, the Netherlands. [2] Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
authors.forename: Derk
authors.initials: D
authors.lastname: Amsen
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D009980:Influenza A virus; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D059467:Transcriptome; D014161:Transduction, Genetic
chemical_list: D051880:Receptors, Notch