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

Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways1. Wnt/β-catenin 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 the induction of Wnt/β-catenin signaling using 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 enabled the generation of CD44(low), CD62L(high), Sca-1(high), CD122(high), Bcl-2(high) self-renewing, multipotent CD8(+) memory stem cells with proliferative and anti-tumor 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 important implications for the design of novel vaccination strategies and adoptive immunotherapies.