Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells

Abstract

Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways1. The Wnt–β-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation2,3, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt–β-catenin signaling by inhibitors of glycogen sythase kinase-3β or the Wnt protein family member Wnt3a arrested CD8+ T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44lowCD62LhighSca-1highCD122highBcl-2high self-renewing multipotent CD8+ memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8+ T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.

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Figure 1: TWS119 activates Wnt signaling in CD8+ T cells.
Figure 2: Wnt signaling inhibits CD8+ T cell proliferation and effector differentiation.
Figure 3: Wnt signaling promotes the generation of TSCM cells.
Figure 4: TSCM cells possess enhanced in vivo recall response and antitumor activity compared to TCM cells and TEM cells.

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Acknowledgements

This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. We would like to thank S.A. Rosenberg, C.A. Klebanoff and S. Kerkar for critical review of the manuscript and A. Mixon and S. Farid of the Flow Cytometry Unit for Flow Cytometry analyses and sorting. This study was done in partial fulfillment of a PhD in Biochemistry (to D.C.P.) at the George Washington University, Washington, DC.

Author information

L.G. designed, performed and analyzed experiments and wrote the paper; X.-S.Z. D.C.P., Y.J., C.S.H., Z.Y., C.W., A.B., L.C., L.M.G., C.M.P. and P.M. performed experiments; and N.P.R. designed experiments and wrote the paper.

Correspondence to Luca Gattinoni or Nicholas P Restifo.

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Gattinoni, L., Zhong, X., Palmer, D. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 15, 808–813 (2009). https://doi.org/10.1038/nm.1982

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