Abstract
The transcriptional repressor Bcl-6 is linked to the development of both CD4(+) T follicular helper (TFH) and central memory T (TCM) cells. Here, we demonstrate that in response to decreased IL-2 signalling, T helper 1 (TH1) cells upregulate Bcl-6 and co-initiate TFH- and TCM-like gene programs, including expression of the cytokine receptors IL-6Rα and IL-7R. Exposure of this potentially bi-potent cell population to IL-6 favours the TFH gene program, whereas IL-7 signalling represses TFH-associated genes including Bcl6 and Cxcr5, but not the TCM-related genes Klf2 and Sell. Mechanistically, IL-7-dependent activation of STAT5 contributes to Bcl-6 repression. Importantly, antigen-specific IL-6Rα(+)IL-7R(+) CD4(+) T cells emerge from the effector population at late time points post influenza infection. These data support a novel role for IL-7 in the repression of the TFH gene program and evoke a divergent regulatory mechanism by which post-effector TH1 cells may contribute to long-term cell-mediated and humoral immunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chromatin Immunoprecipitation
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Flow Cytometry
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Gene Expression Regulation
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Immunoblotting
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Interleukin-2 / metabolism*
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Interleukin-6 / metabolism*
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Interleukin-7 / metabolism*
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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L-Selectin / genetics
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L-Selectin / metabolism
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Mice
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Orthomyxoviridae Infections
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Positive Regulatory Domain I-Binding Factor 1
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Proto-Oncogene Proteins c-bcl-6
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Receptors, CXCR5 / genetics
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Receptors, CXCR5 / metabolism
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Receptors, Interleukin-6 / genetics
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Receptors, Interleukin-6 / metabolism
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Receptors, Interleukin-7 / genetics
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Receptors, Interleukin-7 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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T-Lymphocyte Subsets
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T-Lymphocytes, Helper-Inducer / metabolism
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Th1 Cells / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Bcl6 protein, mouse
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CXCR5 protein, mouse
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DNA-Binding Proteins
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Interleukin-2
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Interleukin-6
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Interleukin-7
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Klf2 protein, mouse
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Kruppel-Like Transcription Factors
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Prdm1 protein, mouse
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Proto-Oncogene Proteins c-bcl-6
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Receptors, CXCR5
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Receptors, Interleukin-6
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Receptors, Interleukin-7
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STAT5 Transcription Factor
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Transcription Factors
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L-Selectin
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Positive Regulatory Domain I-Binding Factor 1