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 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.
Gattinoni
Luca
L
Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. gattinol@mail.nih.gov
Zhong
Xiao-Song
XS
Palmer
Douglas C
DC
Ji
Yun
Y
Hinrichs
Christian S
CS
Yu
Zhiya
Z
Wrzesinski
Claudia
C
Boni
Andrea
A
Cassard
Lydie
L
Garvin
Lindsay M
LM
Paulos
Chrystal M
CM
Muranski
Pawel
P
Restifo
Nicholas P
NP
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
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