Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells
Open accessAbstract
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.
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In more recent mouse work, blocking T cell differentiation via Wnt signaling promoted generation of the memory stem cell population.
“More recent mouse work has shown that by blocking T cell differentiation, Wnt signaling promoted the generation of this memory stem cell population [70].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [70]
PD-1 may mark exhausted cells, Tim-3 and KLRG-1 may mark senescent cells, and mouse stem-like T cells may express Sca-1.
“It is arguable but experimentally operative that PD-1 may be a marker for exhausted cells, Tim-3 and KLRG-1 may be markers for senescent cells, and mouse stem-like T cells may express Sca-1 [70].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [70]
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- Authors
- Gattinoni, L., Zhong, X.-S., Palmer, D. C., Ji, Y., Hinrichs, C. S., Yu, Z., Wrzesinski, C., Boni, A., Cassard, L., Garvin, L. M., Paulos, C. M., Muranski, P., & Restifo, N. P.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gattinoni, Luca
- Restifo, Nicholas P
- ORCID
- Venue
- Nature Medicine
- Published
- 2009-06-14
- Volume
- 15
- Issue
- 7
- Pages
- 808-813
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2707501
- OpenAlex
- W2071548401
- Cited by
- 1,031
- References
- 40
- Citations by year
- 2026: 49 · 2025: 65 · 2024: 65 · 2023: 68 · 2022: 66 · 2021: 74 · 2020: 96 · 2019: 80 · 2018: 64 · 2017: 62 · 2016: 48 · 2015: 56 · 2014: 47 · 2013: 53 · 2012: 39
- FWCI
- 19.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC010763)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- Wnt signaling, Wnt/β-catenin signaling, CD8+ T cells, effector T cell differentiation, naive T cells, glycogen synthase kinase-3β, Wnt3a, T cell self-renewal, antitumor immunity, adoptive immunotherapy, vaccination strategies
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Cell Differentiation, Hematopoietic Stem Cells, Immunologic Memory, Lymphocyte Activation, Mice, Inbred C57BL, Signal Transduction, CD8-Positive T-Lymphocytes, Hyaluronan Receptors, L-Selectin, Glycogen Synthase Kinase 3, Wnt Proteins, beta Catenin, Mice, Hepatocyte Nuclear Factor 1-alpha, T Cell Transcription Factor 1
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