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

Nat Med. 2009 Jul;15(7):808-13. doi: 10.1038/nm.1982. Epub 2009 Jun 14.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / 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


  • 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