Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory

G Jeannet, C Boudousquié, N Gardiol… - Proceedings of the …, 2010 - National Acad Sciences
G Jeannet, C Boudousquié, N Gardiol, J Kang, J Huelsken, W Held
Proceedings of the National Academy of Sciences, 2010National Acad Sciences
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 …
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 β-catenin and γ-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.
National Acad Sciences