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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Vydáno v:	The Journal of immunology (1950) Ročník 193; číslo 11; s. 5480
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.12.2014
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1550-6606 1550-6606
DOI:	10.4049/jimmunol.1303417