TY - JOUR
T1 - A central role for Notch in effector CD8 + T cell differentiation
AU - Backer, Ronald A.
AU - Helbig, Christina
AU - Gentek, Rebecca
AU - Kent, Andrew
AU - Laidlaw, Brian J.
AU - Dominguez, Claudia X.
AU - De Souza, Yevan S.
AU - Van Trierum, Stella E.
AU - Van Beek, Ruud
AU - Rimmelzwaan, Guus F.
AU - Ten Brinke, Anja
AU - Willemsen, A. Marcel
AU - Van Kampen, Antoine H.C.
AU - Kaech, Susan M.
AU - Blander, J. Magarian
AU - Van Gisbergen, Klaas
AU - Amsen, Derk
N1 - Funding Information:
We thank J.C. Zuniga Pflucker (Sunnybrook Research Institute) and D. Vignali (University of Pittsburgh) for the pMIY and pMIY-myr-Akt retroviral expression constructs; T.N.M. Schumacher (Netherlands Cancer Institute) for OVA-influenza; J. den Haan (Free University of Amsterdam) for MyD88-deficient mice; M. Suresh and E.H. Kim for advice on the staining of phosphorylated proteins for flow cytometry; M. Wolkers, M. Nolte, R. van Lier and M. van Ham for suggestions and proofreading of the manuscript; and the tetramer facility of the US National Institutes of Health for tetramers of major histocompatibility complex. Supported by NWO-ALW, the Landsteiner Foundation for Blood Research, the Academic Medical Center (D.A.), the US National Institutes of Health (AI095245 and DK072201 to J.M.B.), the Burroughs Wellcome Trust Fund (J.M.B.), the Leukemia and Lymphoma Society (J.M.B.), the Irma-Hirschl Charitable Trust and Monique Weill-Caulier Charitable Trust (J.M.B.).
PY - 2014/11/18
Y1 - 2014/11/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84911171912&partnerID=8YFLogxK
U2 - 10.1038/ni.3027
DO - 10.1038/ni.3027
M3 - Article
C2 - 25344724
AN - SCOPUS:84911171912
SN - 1529-2908
VL - 15
SP - 1143
EP - 1151
JO - Nature immunology
JF - Nature immunology
IS - 12
ER -