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

TitleA central role for Notch in effector CD8(+) T cell differentiation.
Publication TypeJournal Article
Year of Publication2014
AuthorsBacker, RA, Helbig, C, Gentek, R, Kent, A, Laidlaw, BJ, Dominguez, CX, de Souza, YS, van Trierum, SE, van Beek, R, Rimmelzwaan, GF, Brinke, Aten, A Willemsen, M, van Kampen, AHC, Kaech, SM, J Blander, M, van Gisbergen, K, Amsen, D
JournalNat Immunol
Volume15
Issue12
Pagination1143-51
Date Published2014 Dec
ISSN1529-2916
KeywordsAdaptive Immunity, Adoptive Transfer, Animals, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Separation, Flow Cytometry, Influenza A virus, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Orthomyxoviridae Infections, Real-Time Polymerase Chain Reaction, Receptors, Notch, T-Lymphocyte Subsets, Transcriptome, Transduction, Genetic
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.

DOI10.1038/ni.3027
Alternate JournalNat. Immunol.
PubMed ID25344724
PubMed Central IDPMC4232996
Grant ListP01 DK072201 / DK / NIDDK NIH HHS / United States
R01 AI095245 / AI / NIAID NIH HHS / United States