title: A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet.
abstract: T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8(+) T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. The loss of both T-bet and Blimp-1 leads to abrogated cytotoxic function and ectopic IL-17 production in CD8(+) T cells. Overall, our data reveal two major overlapping pathways of effector differentiation governed by the availability of Blimp-1 and T-bet and suggest a model for cytokine-induced transcriptional changes that combine, quantitatively and qualitatively, to promote robust effector CD8(+) T cell differentiation.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Annie
authors.initials: A
authors.lastname: Xin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Frederick
authors.initials: F
authors.lastname: Masson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liao
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Preston
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Tianxia
authors.initials: T
authors.lastname: Guan
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Renee
authors.initials: R
authors.lastname: Gloury
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Moshe
authors.initials: M
authors.lastname: Olshansky
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Lin
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Terence P
authors.initials: TP
authors.lastname: Speed
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gordon K
authors.identifier: http://orcid.org/0000-0001-9221-2892
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: The Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria, Australia.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
mesh_terms: D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000276:immunology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D053118:Influenza A Virus, H1N1 Subtype; D018664:Interleukin-12 / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D060888:Real-Time Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000276:immunology; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D007376:Interleukin-2; C513258:Prdm1 protein, mouse; D050797:STAT4 Transcription Factor; D050799:STAT5 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D018664:Interleukin-12; D000074462:Positive Regulatory Domain I-Binding Factor 1