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PMID: 19525962 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

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

Nature medicine ·Vol. 15 ·No. 7 ·2009-07-00 ·Pages 808-13

Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzesinski C, Boni A, Cassard L, Garvin LM, Paulos CM, Muranski P, Restifo NP

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.

MeSH Terms
Animals CD8-Positive T-Lymphocytes/cytology,physiology Cell Differentiation Glycogen Synthase Kinase 3/antagonists & inhibitors Glycogen Synthase Kinase 3 beta Hematopoietic Stem Cells/physiology Hepatocyte Nuclear Factor 1-alpha Hyaluronan Receptors/analysis Immunologic Memory L-Selectin/analysis Lymphocyte Activation Mice Mice, Inbred C57BL Signal Transduction/physiology T Cell Transcription Factor 1/physiology Wnt Proteins/physiology beta Catenin/physiology
Chemicals
Cd44 protein, mouse Hepatocyte Nuclear Factor 1-alpha Hnf1a protein, mouse Hyaluronan Receptors T Cell Transcription Factor 1 Wnt Proteins beta Catenin L-Selectin Glycogen Synthase Kinase 3 beta Glycogen Synthase Kinase 3
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Gattinoni Luca
Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA. gattinol@mail.nih.gov
Zhong Xiao-Song
Palmer Douglas C
Ji Yun
Hinrichs Christian S
Yu Zhiya
Wrzesinski Claudia
Boni Andrea
Cassard Lydie
Garvin Lindsay M
Paulos Chrystal M
Muranski Pawel
Restifo Nicholas P
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.1982
Email
gattinol@mail.nih.gov
Published
2009-07-00
Epub
2009-00-14
Pages
808-13
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC2707501
Subset
IM
Grants
Intramural NIH HHS · Z01 BC010763-02 · United States
Corrections
CommentIn
PMID: 19584859
CommentIn
PMID: 20448567
External Links
PubMed source DOI: 10.1038/nm.1982 PMC Full Text View journal details
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