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Nat Immunol. 2014 Dec;15(12):1143-51. doi: 10.1038/ni.3027. Epub 2014 Oct 26.

A central role for Notch in effector CD8(+) T cell differentiation.

Author information

1
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.
2
Department of Cell Biology and Histology, Academic Medical Center, Amsterdam, the Netherlands.
3
The Icahn School of Medicine at Mount Sinai, Immunology Institute and Tisch Cancer Institute, Department of Medicine, New York, New York, USA.
4
Department of Immunobiology and Howard Hughes Medical Institute, Yale University, School of Medicine, New Haven, Connecticut, USA.
5
Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands; Viroclinics Biosciences BV, Rotterdam, the Netherlands.
6
Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.
7
Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands.
8
Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands.

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.

PMID:
25344724
PMCID:
PMC4232996
DOI:
10.1038/ni.3027
[Indexed for MEDLINE]
Free PMC Article

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