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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arenaviridae Infections / immunology
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CD8-Positive T-Lymphocytes / immunology*
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Cell Differentiation / immunology*
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Chromatin Immunoprecipitation
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Cytokines / immunology
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Flow Cytometry
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Gene Expression Profiling
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Influenza A Virus, H1N1 Subtype
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Interleukin-12 / immunology*
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Interleukin-17 / immunology
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Interleukin-2 / immunology*
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Lymphocytic choriomeningitis virus
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Mice
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Orthomyxoviridae Infections / immunology
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Positive Regulatory Domain I-Binding Factor 1
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Real-Time Polymerase Chain Reaction
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STAT4 Transcription Factor / immunology
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STAT5 Transcription Factor / immunology
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Sequence Analysis, RNA
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Signal Transduction
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T-Box Domain Proteins / immunology*
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Transcription Factors / immunology*
Substances
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Cytokines
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Interleukin-17
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Interleukin-2
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Prdm1 protein, mouse
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STAT4 Transcription Factor
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STAT5 Transcription Factor
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Stat4 protein, mouse
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Transcription Factors
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Interleukin-12
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Positive Regulatory Domain I-Binding Factor 1