title: T Cell factor 1 represses CD8+ effector T cell formation and function.
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.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands.
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Tiemessen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands.
authors.forename: Miranda R M
authors.initials: MR
authors.lastname: Baert
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands.
authors.forename: Lianne
authors.initials: L
authors.lastname: Kok
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands.
authors.forename: Marja C J A
authors.initials: MC
authors.lastname: van Eggermond
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van den Elsen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC/Leiden, the Netherlands f.j.t.staal@lumc.nl.
authors.forename: Frank J T
authors.initials: FJ
authors.lastname: Staal
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D019175:DNA Methylation; D018628:Gene Dosage; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D055550:Protein Stability; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D019562:Viral Load; D014777:Virus Diseases; D000098815:T-bet Transcription Factor
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C087042:PRDM1 protein, human; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1