Expressing a stabilized form of β-catenin extends the lifespan of regulatory T cells— one goal of therapies that take advantage of these cells (pages 162–169).
The vital role of regulatory T (Treg) cells in maintaining self-tolerance is exquisitely clear1. Defects in Treg cell development lead to systemic autoimmunity and early death in both mice and humans. Despite the importance of these cells in immune homeostasis, the intracellular events that control Treg cell activation and survival have not been elucidated—nor have the processes that control proliferative unresponsiveness in both Treg cells and anergic T cells. Anergic T cells are functionally inactivated after an antigen encounter, but remain alive in a hyporesponsive state.
In this issue of Nature Medicine, Ding et al.2 enhance the survival of Treg cells in vitro and in vivo by ectopically expressing a stabilized form of β-catenin (sβ-catenin). These transduced Treg cells provided improved protection when adoptively transferred into a mouse model of autoimmune colitis. In addition, transduction of sβ-catenin into conventional CD4+CD25− T cells led to an anergic phenotype in which normal T cell responses were suppressed. The investigators suggest that the activation of the canonical Wnt pathway is essential in Treg cell homeostasis and may have a key role in anergy induction in matured T cells2.
Wnt- or Fz-initiated signaling is an evolutionarily conserved pathway implicated in a range of basic cellular processes, including cell differentiation, proliferation and apoptosis3. The canonical Wnt pathway directly controls the cytosolic levels of the proto-oncoprotein β-catenin via a so-called 'destruction complex'. This complex is formed by several enzyme and scaffolding molecules, including the active serine-threonine kinase glycogen synthase kinase-3β (GSK-3β; Fig. 1)3. Phosphorylation of β-catenin by GSK-3β leads to its ubiquitinylation and degradation. Thus, mutant nonphosphorylated forms of β-catenin stabilize the molecule and allow for nuclear localization and activation of general and cell-specific target genes3.
Ding et al.2 found that ectopic expression of sβ-catenin mediated increased survival and anergy induction through the regulation of several anti-apoptotic and survival proteins including Grail, Itch, Cbl-b and Bcl-XL (but not another family member, Bcl-2). Thus, rather than altering Treg cell activity, the expression of these survival proteins is thought to increase the longevity of the adoptively transferred Treg cells, leading to the protective effects observed in the colitis model.
Under normal physiological conditions, Treg cell activation depends on T cell receptor (TCR) engagement followed by CD28-mediated costimulatory signals. Once Treg cells are activated, their long-term survival requires continued TCR-CD28 engagement as well as IL-2–mediated signaling1. Thus, it is not surprising that disruption of either the TCR-CD28 or the IL-2 pathway leads to reduced Treg cell survival and concomitant systemic autoimmunity. However, these two pathways differ in that CD28 acts through Bcl-XL, whereas IL-2 acts through Bcl-2 (ref. 4). Thus, the effects observed with sβ-catenin and the CD28 costimulation-mediated Treg cell survival pathways1 may be linked (Fig. 1). This possibility is supported by previous results from Diehn et al.5 showing that CD28 signaling promotes phosphorylation, and thus inactivation, of GSK-3β, which may in turn lead to stabilization of β-catenin activity and thus enhanced Treg cell survival. Future studies will be needed to explore the potential biochemical links between β-catenin function and CD28-mediated signal transduction in Treg cells.
The findings emphasize the potential to use sβ-catenin as a modulator of Treg cell survival in adoptive cell therapy strategies. Certainly, there has been increasing interest in the use of expanded Treg cells, especially antigen-specific Treg cells, as therapeutics. Any approach that will help maintain the longevity of the cells would have potential clinical implications.
As the authors point out, a possible concern regarding this approach is that activation of canonical Wnt signaling can cause cancer in multiple tissues6. In the hematopoietic system, for instance, canonical and noncanonical Wnt signaling has been implicated in the maintenance of the stem cell niche, and increased canonical activity occurs in certain forms of leukemia7,8. Wnt signaling, however, elicits different effects in distinct cell types, and Ding et al. did not observe increased tumorigenic potential of the sβ-catenin transduced Treg cells or conventional T cells2.
This lack of tumorigenicity could be explained by the decreased expression of c-Myc in this setting9. c-Myc is an oncoprotein whose expression is often upregulated by β-catenin signaling. Future studies that include longer activation periods or combine sβ-catenin transduction with the expression of known lymphocytic oncogenes will be needed to fully determine the tumorigenic potential of these T cells.
In light of the new findings, the role of the Wnt pathway should be thoroughly investigated in Treg cells and conventional T cells, especially in the tolerance setting. Multiple studies show that β-catenin is important in T cell development in the thymus8,10,11. Expression or disruption of sβ-catenin has dramatic effects on early thymocyte development, altering the development of CD4−CD8− early T cell precursors as well as the development of maturing CD4+CD8+ thymocytes when altered forms of the protein are conditionally expressed. What has not yet been examined is the consequence of sβ-catenin expression at the decision points at which mature CD4+ T cells branch into the Foxp3 lineage that distinguishes Treg cells from the other T cell populations12.
It would have been interesting to see the normal expression pattern of active, dephosphorylated β-catenin in Treg cells and conventional CD4+CD25− T cells before and after activation, and to examine how sβ-catenin affects early stages of Treg cell development. Does the level of canonical Wnt signaling change during the differentiation or maturation of these cells? Does activation of T cells change the level of nuclear β-catenin, and is this process dependent on the Wnt ligand? What happens if β-catenin is knocked down or other members of the Wnt signaling cascade are altered in mature Treg cells?
In this regard, Rudensky and his colleagues have shown that 'Foxp3-less wannabe' Treg cells share features of the ectopically sβ-catenin–transduced CD4+CD25− conventional T cells, including the inability to produce IL-2 and T helper type 1 and T helper type 2 cytokines, and an anergic phenotype13. Is the anergy phenotype a physiological reflection of the consequences of aberrant TCR signaling during Treg and tolerant T cell differentiation?
Any efforts to enhance or extend the effects of Treg cells for the treatment of autoimmune disease and transplant rejection in vivo will depend on a better understanding of the role of the Wnt pathway in peripheral T cell function.
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Bluestone, J., Hebrok, M. Safer, longer-lasting regulatory T cells with β-catenin. Nat Med 14, 118–119 (2008). https://doi.org/10.1038/nm0208-118
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