title: 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 pathways. The Wnt-beta-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt-beta-catenin signaling by inhibitors of glycogen sythase kinase-3beta 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 CD44(low)CD62L(high)Sca-1(high)CD122(high)Bcl-2(high) 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.
authors.affiliation: Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. gattinol@mail.nih.gov
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Zhong
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Yun
authors.initials: Y
authors.lastname: Ji
authors.forename: Christian S
authors.initials: CS
authors.lastname: Hinrichs
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Claudia
authors.initials: C
authors.lastname: Wrzesinski
authors.forename: Andrea
authors.initials: A
authors.lastname: Boni
authors.forename: Lydie
authors.initials: L
authors.lastname: Cassard
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Garvin
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051538:Hepatocyte Nuclear Factor 1-alpha; D018960:Hyaluronan Receptors / Q000032:analysis; D007156:Immunologic Memory; D019041:L-Selectin / Q000032:analysis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology*; D051822:T Cell Transcription Factor 1 / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
chemical_list: C476399:Cd44 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D018960:Hyaluronan Receptors; D051822:T Cell Transcription Factor 1; D051153:Wnt Proteins; D051176:beta Catenin; D019041:L-Selectin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3