Title | A central role for Notch in effector CD8(+) T cell differentiation. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Backer, 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 |
Journal | Nat Immunol |
Volume | 15 |
Issue | 12 |
Pagination | 1143-51 |
Date Published | 2014 Dec |
ISSN | 1529-2916 |
Keywords | Adaptive 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. |
DOI | 10.1038/ni.3027 |
Alternate Journal | Nat. Immunol. |
PubMed ID | 25344724 |
PubMed Central ID | PMC4232996 |
Grant List | P01 DK072201 / DK / NIDDK NIH HHS / United States R01 AI095245 / AI / NIAID NIH HHS / United States |