Activation of Wnt signaling arrests effector differentiation in human peripheral and cord blood-derived T lymphocytes

J Immunol. 2011 Nov 15;187(10):5221-32. doi: 10.4049/jimmunol.1101585. Epub 2011 Oct 19.


The canonical Wnt/β-catenin signaling pathway plays an important role in thymocyte development and T cell migration, but little is known about its role in naive-to-effector differentiation in human peripheral T cells. We show that activation of Wnt/β-catenin signaling arrests human peripheral blood and cord blood T lymphocytes in the naive stage and blocks their transition into functional T effector cells. Wnt signaling was induced in polyclonally activated human T cells by treatment either with the glycogen synthase kinase 3β inhibitor TWS119 or the physiological Wnt agonist Wnt-3a, and these T cells preserved a naive CD45RA(+)CD62L(+) phenotype compared with control-activated T cells that progressed to a CD45RO(+)CD62L(-) effector phenotype, and this occurred in a TWS119 dose-dependent manner. TWS119-induced Wnt signaling reduced T cell expansion, as a result of a block in cell division, and impaired acquisition of T cell effector function, measured by degranulation and IFN-γ production in response to T cell activation. The block in T cell division may be attributed to the reduced IL-2Rα expression in TWS119-treated T cells that lowers their capacity to use autocrine IL-2 for expansion. Collectively, our data suggest that Wnt/β-catenin signaling is a negative regulator of naive-to-effector T cell differentiation in human T lymphocytes. The arrest in T cell differentiation induced by Wnt signaling might have relevant clinical applications such as to preserve the naive T cell compartment in Ag-specific T cells generated ex vivo for adoptive T cell immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Fetal Blood / cytology*
  • Fetal Blood / immunology*
  • Fetal Blood / metabolism
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Humans
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / enzymology
  • T-Lymphocyte Subsets / immunology*
  • Wnt Proteins / metabolism
  • Wnt Proteins / physiology*


  • Pyrimidines
  • Pyrroles
  • TWS 119
  • Wnt Proteins
  • Glycogen Synthase Kinase 3