Activation of Wnt signaling arrests effector differentiation in human peripheral and cord blood-derived T lymphocytes.
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.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Sujatha
S
Muralidharan
Patrick J
PJ
Hanley
Enli
E
Liu
Rikhia
R
Chakraborty
Catherine
C
Bollard
Elizabeth
E
Shpall
Cliona
C
Rooney
Barbara
B
Savoldo
John
J
Rodgers
Gianpietro
G
Dotti
D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology*
D011743:Pyrimidines; D011758:Pyrroles; C547688:TWS 119; D051153:Wnt Proteins; D038362:Glycogen Synthase Kinase 3