T Cell factor 1 represses CD8+ effector T cell formation and function
The Wnt-responsive transcription factor T cell factor 1 (Tcf1) is well known for its role in thymic T cell development and the formation of memory CD8(+) T cells. However, its role in the initial phases of CD8(+) T effector cell formation has remained unexplored. We report that high levels of Wnt si...
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| Published in: | The Journal of immunology (1950) Vol. 193; no. 11; p. 5480 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
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United States
01.12.2014
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| ISSN: | 1550-6606, 1550-6606 |
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| Abstract | The Wnt-responsive transcription factor T cell factor 1 (Tcf1) is well known for its role in thymic T cell development and the formation of memory CD8(+) T cells. However, its role in the initial phases of CD8(+) T effector cell formation has remained unexplored. We report that high levels of Wnt signaling and Tcf1 are operational in naive and memory CD8(+) T cells, whereas Wnt signaling and Tcf1 were low in effector CD8(+) T cells. CD8(+) T cells deficient in Tcf1 produce IFN-γ more rapidly, coinciding with increased demethylation of the IFN-γ enhancer and higher expression of the transcription factors Tbet and Blimp1. Moreover, virus-specific Tcf1(-/-) CD8(+) T cells show accelerated expansion in acute infection, which is associated with increased IFN-γ and TNF production and lower viral load. Genetic complementation experiments with various Tcf1 isoforms indicate that Tcf1 dosage and protein stability are critical in suppressing IFN-γ production. Isoforms lacking the β-catenin binding domain are equally effective in inhibiting CD8(+) effector T cell formation. Thus, Tcf1 functions as a repressor of CD8(+) effector T cell formation in a β-catenin/Wnt-independent manner. |
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| AbstractList | The Wnt-responsive transcription factor T cell factor 1 (Tcf1) is well known for its role in thymic T cell development and the formation of memory CD8(+) T cells. However, its role in the initial phases of CD8(+) T effector cell formation has remained unexplored. We report that high levels of Wnt signaling and Tcf1 are operational in naive and memory CD8(+) T cells, whereas Wnt signaling and Tcf1 were low in effector CD8(+) T cells. CD8(+) T cells deficient in Tcf1 produce IFN-γ more rapidly, coinciding with increased demethylation of the IFN-γ enhancer and higher expression of the transcription factors Tbet and Blimp1. Moreover, virus-specific Tcf1(-/-) CD8(+) T cells show accelerated expansion in acute infection, which is associated with increased IFN-γ and TNF production and lower viral load. Genetic complementation experiments with various Tcf1 isoforms indicate that Tcf1 dosage and protein stability are critical in suppressing IFN-γ production. Isoforms lacking the β-catenin binding domain are equally effective in inhibiting CD8(+) effector T cell formation. Thus, Tcf1 functions as a repressor of CD8(+) effector T cell formation in a β-catenin/Wnt-independent manner. The Wnt-responsive transcription factor T cell factor 1 (Tcf1) is well known for its role in thymic T cell development and the formation of memory CD8(+) T cells. However, its role in the initial phases of CD8(+) T effector cell formation has remained unexplored. We report that high levels of Wnt signaling and Tcf1 are operational in naive and memory CD8(+) T cells, whereas Wnt signaling and Tcf1 were low in effector CD8(+) T cells. CD8(+) T cells deficient in Tcf1 produce IFN-γ more rapidly, coinciding with increased demethylation of the IFN-γ enhancer and higher expression of the transcription factors Tbet and Blimp1. Moreover, virus-specific Tcf1(-/-) CD8(+) T cells show accelerated expansion in acute infection, which is associated with increased IFN-γ and TNF production and lower viral load. Genetic complementation experiments with various Tcf1 isoforms indicate that Tcf1 dosage and protein stability are critical in suppressing IFN-γ production. Isoforms lacking the β-catenin binding domain are equally effective in inhibiting CD8(+) effector T cell formation. Thus, Tcf1 functions as a repressor of CD8(+) effector T cell formation in a β-catenin/Wnt-independent manner.The Wnt-responsive transcription factor T cell factor 1 (Tcf1) is well known for its role in thymic T cell development and the formation of memory CD8(+) T cells. However, its role in the initial phases of CD8(+) T effector cell formation has remained unexplored. We report that high levels of Wnt signaling and Tcf1 are operational in naive and memory CD8(+) T cells, whereas Wnt signaling and Tcf1 were low in effector CD8(+) T cells. CD8(+) T cells deficient in Tcf1 produce IFN-γ more rapidly, coinciding with increased demethylation of the IFN-γ enhancer and higher expression of the transcription factors Tbet and Blimp1. Moreover, virus-specific Tcf1(-/-) CD8(+) T cells show accelerated expansion in acute infection, which is associated with increased IFN-γ and TNF production and lower viral load. Genetic complementation experiments with various Tcf1 isoforms indicate that Tcf1 dosage and protein stability are critical in suppressing IFN-γ production. Isoforms lacking the β-catenin binding domain are equally effective in inhibiting CD8(+) effector T cell formation. Thus, Tcf1 functions as a repressor of CD8(+) effector T cell formation in a β-catenin/Wnt-independent manner. |
| Author | Tiemessen, Machteld M Baert, Miranda R M Staal, Frank J T Arens, Ramon van den Elsen, Peter J van Eggermond, Marja C J A Kok, Lianne |
| Author_xml | – sequence: 1 givenname: Machteld M surname: Tiemessen fullname: Tiemessen, Machteld M organization: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands – sequence: 2 givenname: Miranda R M surname: Baert fullname: Baert, Miranda R M organization: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands – sequence: 3 givenname: Lianne surname: Kok fullname: Kok, Lianne organization: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands – sequence: 4 givenname: Marja C J A surname: van Eggermond fullname: van Eggermond, Marja C J A organization: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands – sequence: 5 givenname: Peter J surname: van den Elsen fullname: van den Elsen, Peter J organization: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands – sequence: 6 givenname: Ramon surname: Arens fullname: Arens, Ramon organization: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands – sequence: 7 givenname: Frank J T surname: Staal fullname: Staal, Frank J T email: f.j.t.staal@lumc.nl organization: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands f.j.t.staal@lumc.nl |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25355919$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Animals CD8-Positive T-Lymphocytes - immunology Cells, Cultured Cytotoxicity, Immunologic DNA Methylation Gene Dosage Hepatocyte Nuclear Factor 1-alpha - genetics Hepatocyte Nuclear Factor 1-alpha - metabolism Immunologic Memory Interferon-gamma - genetics Interferon-gamma - metabolism Lymphocytic Choriomeningitis - immunology Lymphocytic choriomeningitis virus - immunology Mice Mice, Inbred C57BL Mice, Knockout Positive Regulatory Domain I-Binding Factor 1 Protein Stability Repressor Proteins - genetics Repressor Proteins - metabolism T-Box Domain Proteins - genetics T-Box Domain Proteins - metabolism Up-Regulation Viral Load Virus Diseases |
| Title | T Cell factor 1 represses CD8+ effector T cell formation and function |
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