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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Bibliographic Details
Published in:The Journal of immunology (1950) Vol. 193; no. 11; p. 5480
Main Authors: Tiemessen, Machteld M, Baert, Miranda R M, Kok, Lianne, van Eggermond, Marja C J A, van den Elsen, Peter J, Arens, Ramon, Staal, Frank J T
Format: Journal Article
Language:English
Published: United States 01.12.2014
Subjects:
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
ISSN:1550-6606, 1550-6606
Online Access:Get more information
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Summary: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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ISSN:1550-6606
1550-6606
DOI:10.4049/jimmunol.1303417