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

The Wnt pathway has a central role in stem cell regulation. Gattinoni et al. now show that activation of the Wnt signaling cascade in naive CD8+ T cells blocks their differentiation into effector T cells and triggers instead a memory stem cell–like phenotype. These T memory stem cells show enhanced antitumor efficacy in mice compared with other T cell subsets, arguing for their further evaluation in adoptive immunotherapies ( pages 731–732 ). 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.