Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells
By L. Gattinoni, Xiaorong Zhong, D. Palmer, Yun Ji, C. Hinrichs, Zhiya Yu, Claudia Wrzesinski, Andrea Boni, L. Cassard, Lindsay Church and 3 more. Nature Medicine, 2009
1,010 citations recorded by the source corpus.
Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways. The Wnt–β-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–β-catenin signaling by 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 promoted the generation of CD44lowCD62LhighSca-1highCD122highBcl-2high 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.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/ba7ea9071c7f49f7cba033aaeb195bebef1ad039
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Citations in the corpus
- From Vaccines to Memory and Back (2010, positive): “Recent studies identified signaling pathways that appear to be involved in the differentiation of memory stem cells as well as drugs that favor the generation of T CM cells (Araki et al., 2009; Gattinoni et al., 2009; Pearce et al., 2009).”
- T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment (2013, background): “More recent mouse work has shown that by blocking T cell differentiation, Wnt signaling promoted the generation of this memory stem cell population [70].”
- Defining T cell states associated with response to checkpoint immunotherapy in melanoma (2018, positive): “Finally, our results also agree with recent studies showing a reduction in open chromatin regions at TCF7 sites in non-programmable, dysfunctional PD-1high T cells (Philip et al., 2017) and with the importance of TCF7 role for WNT signaling in stem cell-like memory cells (Gattinoni et al., 2009).”
- Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo (2015, positive): “Pharmacologic activation of Wnt signaling during the culture of CD8 + T N arrests differentiation at a phenotype intermediate between T N and T CM , and these arbitrarily termed “memory stem cells” have potent antitumor activity in animals 47 .”
- A human memory T-cell subset with stem cell-like properties (2011, background): “The recent identification in mice of a population of memory T cells with enhanced stem cell–like qualities compared with conventional T CM cells adds complexity to this dichotomous vie”
- Wnt/beta-catenin pathway: modulating anticancer immune response (2017, background): “On the other hand, induction of Wnt signaling has shown to be important in maintenance of stemness of memory CD8 T cells by blocking T cell differentiation [95].”
- Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1 (2010, background): “This is also true for in vitro TCRstimulated T cells; however, when combined with pharmacologically stabilized b-catenin, TCF-1 downregulation was blocked (Gattinoni et al., 2009).”