Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory.
Immune protection from intracellular pathogens depends on the generation of terminally differentiated effector and of multipotent memory precursor CD8 T cells, which rapidly regenerate effector and memory cells during recurrent infection. The identification of factors and pathways involved in CD8 T cell differentiation is of obvious importance to improve vaccination strategies. Here, we show that mice lacking T cell factor 1 (Tcf-1), a nuclear effector of the canonical Wingless/Integration 1 (Wnt) signaling pathway, mount normal effector and effector memory CD8 T cell responses to infection with lymphocytic choriomeningitis virus (LCMV). However, Tcf-1-deficient CD8 T cells are selectively impaired in their ability to expand upon secondary challenge and to protect from recurrent virus infection. Tcf-1-deficient mice essentially lack CD8 memory precursor T cells, which is evident already at the peak of the primary response, suggesting that Tcf-1 programs CD8 memory cell fate. The function of Tcf-1 to establish CD8 T cell memory is dependent on the catenin-binding domain in Tcf-1 and requires the Tcf-1 coactivators and Wnt signaling intermediates beta-catenin and gamma-catenin. These findings demonstrate that the canonical Wnt signaling pathway plays an essential role for CD8 central memory T cell differentiation under physiological conditions in vivo. They raise the possibility that modulation of Wnt signaling may be exploited to improve the generation of CD8 memory T cells during vaccination or for therapies designed to promote sustained cytotoxic CD8 T cell responses against tumors.
Jeannet
Grégoire
G
Ludwig Institute for Cancer Research Ltd., Lausanne Branch and University of Lausanne, Epalinges, Switzerland.
Boudousquié
Caroline
C
Gardiol
Noémie
N
Kang
Joonsoo
J
Huelsken
Joerg
J
Held
Werner
W
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D051538:Hepatocyte Nuclear Factor 1-alpha; D007156:Immunologic Memory; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1 / Q000172:deficiency / Q000276:immunology*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000276:immunology / Q000378:metabolism; D051185:gamma Catenin / Q000276:immunology / Q000378:metabolism
D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D051822:T Cell Transcription Factor 1; D051153:Wnt Proteins; D051176:beta Catenin; D051185:gamma Catenin
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