The binding of WNT proteins to their receptor complexes leads to an accumulation of intracellular β-catenin, which enters the nucleus and promotes the transcription of target genes mediated by T cell factor 1 and lymphocyte enhancer-binding factor 1. WNT signalling can be mimicked by using an inhibitor of glycogen synthase kinase 3β (GSK3β), an enzyme that is involved in the degradation of β-catenin. The authors found that stimulation of naive CD8+ T cells in the presence of GSK3β inhibitors arrested their proliferation and differentiation into effector T cells in vitro. Specifically, the T cells failed to upregulate CD44 and downregulate CD62L expression, and showed decreased cytotoxic effector functions. Similar effects were observed when CD8+ T cells were primed in the presence of the WNT protein WNT3A.
Consistent with the in vitro findings, adoptive transfer of CD8+ T cells in the presence of the GSK3β inhibitor led to impaired induction of effector T cells in response to vaccination. However, the authors noted an increase in the generation of CD8+ T cells with a CD44lowCD62LhiSCA1+BCL-2+CD122+ phenotype — which is characteristic of a previously described population of cells designated T memory stem (TSCM) cells. These TSCM cells could be distinguished from naive T cells by their superior cell cycling capacity, their ability to rapidly release cytokines such as interferon-γ and interleukin-2 (IL-2) after antigen encounter and their persistence in MHC class I-deficient hosts. Further evaluation of the fate of these TSCM cells indicated that they could self renew and differentiate into various memory and effector CD8+ T cell subsets following serial transplantation into sublethally irradiated recipient mice. So, WNT signalling promotes the generation of a stem cell-like population of self-renewing, multipotent memory T cells.
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