Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

WNT signalling in the immune system: WNT is spreading its wings

Nature Reviews Immunology volume 8, pages 581–593 (2008)Cite this article

A Corrigendum to this article was published on 07 April 2015

This article has been updated

Key Points

  • There are different WNT signalling pathways: the canonical WNT pathway, which involves β-catenin and members of the T-cell factor (TCF)/lymphocyte-enhancer-binding factor (LEF) family, the planar cell polarity (PCP) pathway and the WNT–Ca2+ pathway.

  • Most studies of immune and blood cells concern canonical WNT signalling.

  • WNT signalling probably controls aspects of haematopoietic stem cell (HSC) self-renewal, although there are some controversies surrounding this topic. The level of WNT signalling seems to be important.

  • WNT signalling is required for T-cell development in the thymus and might also be involved in developing B cells in the bone marrow.

  • WNT signalling regulates aspects of peripheral T-cell activation and migration.

  • WNT signalling is also involved in dendritic cell (DC) maturation, and activation of WNT signalling increases the survival of regulatory T cells.

  • Dysregulated WNT signalling can cause leukaemia.

Abstract

WNT proteins are secreted morphogens that are required for basic developmental processes, such as cell-fate specification, progenitor-cell proliferation and the control of asymmetric cell division, in many different species and organs. In blood and immune cells, WNT signalling controls the proliferation of progenitor cells and might also affect the cell-fate decisions of stem cells. Recent studies indicate that WNT proteins also regulate effector T-cell development, regulatory T-cell activation and dendritic-cell maturation. WNT signalling seems to function as a universal mechanism in leukocytes to establish a pool of undifferentiated cells for further selection, effector-cell maturation and terminal differentiation. WNT signalling is therefore subject to strict molecular control, and dysregulated WNT signalling is implicated in the development of haematological malignancies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Canonical or WNT–β-catenin–TCF/LEF signalling.
Figure 2: Non-canonical WNT signalling.
Figure 3: The potential role of WNT in the stem-cell niche.
Figure 4: WNT signalling in the thymus.
Figure 5: WNT in T-cell migration.

Similar content being viewed by others

Change history

  • 07 April 2015

    On page 589 of this article, in the paragraph with the subheading "WNT signalling in antigen-presenting cells", the authors state the following: "The functional role of WNT5A and its receptor Frizzled-5 during infection consisted of inhibition of the antigen-specific T helper 1 (TH1)-cell response, namely inhibition of IL-12 production and of the subsequent generation of interferon-γ (IFNγ)-producing T cells84”. This should have read: "The functional role of WNT5A and its receptor Frizzled-5 during infection consisted of enhancement of the antigen specific T helper 1 (TH1)-cell response, namely an increase in IL- 12 production and the subsequent generation of interferon-γ (IFNγ)-producing T cells84". In line with this, in Figure 5, the arrow from WNT5A to IL-12 production should indicate stimulation rather than inhibition of this process. The last sentence of the legend of Figure 5 should read as follows: "If the migrated T cells produce interleukin-4 (IL-4), they stimulate the DCs to produce WNT5A, which in turn stimulates the production of IL-12 and the subsequent induction of interferon-γ-producing T helper 1 cells (TH1 cells)". The authors apologize for this error, which has now been corrected online.

References

  1. Nusse, R. et al. A new nomenclature for int-1 and related genes: the Wnt gene family. Cell 64, 231 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Nusse, R., van Ooyen, A., Cox, D., Fung, Y. K. & Varmus, H. Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15. Nature 307, 131–136 (1984).

    Article  CAS  PubMed  Google Scholar 

  3. Staal, F. J. & Clevers, H. C. WNT signalling and haematopoiesis: a WNT–WNT situation. Nature Rev. Immunol. 5, 21–30 (2005).

    Article  CAS  Google Scholar 

  4. Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Staal, F. J., Weerkamp, F., Langerak, A. W., Hendriks, R. W. & Clevers, H. C. Transcriptional control of T lymphocyte differentiation. Stem Cells 19, 165–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Timm, A. & Grosschedl, R. Wnt signaling in lymphopoiesis. Curr. Top. Microbiol. Immunol. 290, 225–252 (2005).

    CAS  PubMed  Google Scholar 

  7. Staal, F. J. & Clevers, H. C. Wnt signaling in the thymus. Curr. Opin. Immunol. 15, 204–208 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Brembeck, F. H., Rosario, M. & Birchmeier, W. Balancing cell adhesion and Wnt signaling, the key role of β-catenin. Curr. Opin. Genet. Dev. 16, 51–59 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Clevers, H. Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Aberle, H., Bauer, A., Stappert, J., Kispert, A. & Kemler, R. β-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16, 3797–3804 (1997).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Roose, J. et al. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 395, 608–612 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Zeng, X. et al. Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 135, 367–375 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Zeng, X. et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438, 873–877 (2005). A key publication showing that in addition to having a negative-regulatory role in the destruction complex, GSK3β also functions as a positive mediator of WNT signalling at the plasma membrane.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Macdonald, B. T., Semenov, M. V. & He, X. Snapshot: Wnt/β-catenin signaling. Cell 131, 1204 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Davidson, G. et al. Casein kinase 1-γ couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438, 867–872 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Staal, F. J., Noort van, M., Strous, G. J. & Clevers, H. C. Wnt signals are transmitted through N-terminally dephosphorylated β-catenin. EMBO Rep. 3, 63–68 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Staal, F. J. et al. Wnt target genes identified by DNA microarrays in immature CD34+ thymocytes regulate proliferation and cell adhesion. J. Immunol. 172, 1099–1108 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Daniels, D. L. & Weis, W. I. ICAT inhibits β-catenin binding to Tcf/Lef-family transcription factors and the general coactivator p300 using independent structural modules. Mol. Cell 10, 573–584 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. van de Wetering, M. et al. The human T cell transcription factor-1 gene. Structure, localization, and promoter characterization. J. Biol. Chem. 267, 8530–8536 (1992).

    CAS  PubMed  Google Scholar 

  20. Liang, H. et al. Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 4, 349–360 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Liang, H. et al. Noncanonical Wnt signaling promotes apoptosis in thymocyte development. J. Exp. Med. 204, 3077–3084 (2007). A study investigating the non-canonical WNT5A gene, which induces apoptosis and counteracts the canonical WNT pathway in thymocytes.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Semenov, M. V., Habas, R., Macdonald, B. T. & He, X. Snapshot: noncanonical Wnt signaling pathways. Cell 131, 1378 (2007).

    Article  PubMed  Google Scholar 

  23. Endo, Y. et al. Wnt-3a-dependent cell motility involves RhoA activation and is specifically regulated by dishevelled-2. J. Biol. Chem. 280, 777–786 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Kuhl, M., Sheldahl, L. C., Park, M., Miller, J. R. & Moon, R. T. The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet. 16, 279–283 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Sheldahl, L. C. et al. Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos. J. Cell Biol. 161, 769–777 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Clipstone, N. A. & Crabtree, G. R. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357, 695–697 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Graef, I. A., Chen, F. & Crabtree, G. R. NFAT signaling in vertebrate development. Curr. Opin. Genet. Dev. 11, 505–512 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Murphy, L. L. & Hughes, C. C. Endothelial cells stimulate T cell NFAT nuclear translocation in the presence of cyclosporin A: involvement of the wnt/glycogen synthase kinase-3-β pathway. J. Immunol. 169, 3717–3725 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Blank, U., Karlsson, G. & Karlsson, S. Signaling pathways governing stem-cell fate. Blood 111, 492–503 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Austin, T. W., Solar, G. P., Ziegler, F. C., Liem, L. & Matthews, W. A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells. Blood 89, 3624–3635 (1997).

    CAS  PubMed  Google Scholar 

  31. Van Den Berg, D. J., Sharma, A. K., Bruno, E. & Hoffman, R. Role of members of the Wnt gene family in human hematopoiesis. Blood 92, 3189–3202 (1998).

    CAS  PubMed  Google Scholar 

  32. Rattis, F. M., Voermans, C. & Reya, T. Wnt signaling in the stem cell niche. Curr. Opin. Hematol. 11, 88–94 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003). This study shows that overexpression of activated β-catenin expands the pool of haematopoietic stem and progenitor cells and increases in vivo repopulation capacity.

    Article  CAS  PubMed  Google Scholar 

  34. Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Baba, Y., Garrett, K. P. & Kincade, P. W. Constitutively active β-catenin confers multilineage differentiation potential on lymphoid and myeloid progenitors. Immunity 23, 599–609 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Fleming, H. E. et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell 2, 274–283 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Scheller, M. et al. Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation. Nature Immunol. 7, 1037–1047 (2006).

    Article  CAS  Google Scholar 

  38. Kirstetter, P., Anderson, K., Porse, B. T., Jacobsen, S. E. & Nerlov, C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nature Immunol. 7, 1048–1056 (2006). References 37 and 38 showed exhaustion of the HSC pool and a multilineage differentiation block using an in vivo model to induce stabilization of β-catenin.

    Article  CAS  Google Scholar 

  39. Nemeth, M. J., Topol, L., Anderson, S. M., Yang, Y. & Bodine, D. M. Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc. Natl Acad. Sci. USA 104, 15436–15441 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cobas, M. et al. β-catenin is dispensable for hematopoiesis and lymphopoiesis. J. Exp. Med. 199, 221–229 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Jeannet, G. et al. Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142–149 (2007). In this study, simultaneous loss of β-catenin and its homologue γ-catenin does not affect haematopoiesis and lymphopoiesis, but WNT signalling was shown to remain largely intact.

    Article  CAS  PubMed  Google Scholar 

  42. Koch, U. et al. Simultaneous loss of β- and γ-catenin does not perturb hematopoiesis or lymphopoiesis. Blood 111, 160–164 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Park, J. I. et al. Frodo links Dishevelled to the p120-catenin/Kaiso pathway: distinct catenin subfamilies promote Wnt signals. Dev. Cell 11, 683–695 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Zhao, C. et al. Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12, 528–541 (2007). In this study, conditional deletion of β-catenin impaired long-term growth and maintenance of HSCs. Deletion of β-catenin also decreased the susceptibility of mice to develop BCR–ABL-induced CML but not ALL.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Trowbridge, J. J., Xenocostas, A., Moon, R. T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nature Med. 12, 89–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Kim, I., Saunders, T. L. & Morrison, S. J. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470–483 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Scollay, R., Bartlett, P. & Shortman, K. T cell development in the adult murine thymus: changes in the expression of the surface antigens Ly2, L3T4 and B2A2 during development from early precursor cells to emigrants. Immunol. Rev. 82, 79–103 (1984).

    Article  CAS  PubMed  Google Scholar 

  48. Weerkamp, F. et al. Age-related changes in the cellular composition of the thymus in children. J. Allergy Clin. Immunol. 115, 834–840 (2005).

    Article  PubMed  Google Scholar 

  49. Dik, W. A. et al. New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling. J. Exp. Med. 201, 1715–1723 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Weerkamp, F., Pike-Overzet, K. & Staal, F. J. T-sing progenitors to commit. Trends Immunol. 27, 125–131 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Staal, F. J. et al. Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription. Eur. J. Immunol. 31, 285–293 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Mulroy, T., McMahon, J. A., Burakoff, S. J., McMahon, A. P. & Sen, J. Wnt-1 and Wnt-4 regulate thymic cellularity. Eur. J. Immunol. 32, 967–971 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Okamura, R. M. et al. Redundant regulation of T cell differentiation and TCRα gene expression by the transcription factors LEF-1 and TCF-1. Immunity 8, 11–20 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Verbeek, S. et al. An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature 374, 70–74 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Reya, T. et al. Wnt signaling regulates B lymphocyte proliferation through a LEF-1 dependent mechanism. Immunity 13, 15–24 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. van de Wetering, M. et al. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88, 789–799 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Behrens, J. et al. Functional interaction of β-catenin with the transcription factor LEF-1. Nature 382, 638–642 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Huber, O. et al. Nuclear localization of β-catenin by interaction with transcription factor LEF-1. Mech. Dev. 59, 3–10 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Schilham, M. W. et al. Critical involvement of Tcf-1 in expansion of thymocytes. J. Immunol. 161, 3984–3991 (1998).

    CAS  PubMed  Google Scholar 

  60. Schmitt, T. M. & Zuniga-Pflucker, J. C. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17, 749–756 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Jaleco, A. C. et al. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J. Exp. Med. 194, 991–1002 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Rothenberg, E. V., Moore, J. E. & Yui, M. A. Launching the T-cell-lineage developmental programme. Nature Rev. Immunol. 8, 9–21 (2008).

    Article  CAS  Google Scholar 

  63. Rothenberg, E. V. Negotiation of the T lineage fate decision by transcription-factor interplay and microenvironmental signals. Immunity 26, 690–702 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Ciofani, M. & Zuniga-Pflucker, J. C. The thymus as an inductive site for T lymphopoiesis. Annu. Rev. Cell. Dev. Biol. 23, 463–493 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Petrie, H. T. & Zuniga-Pflucker, J. C. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu. Rev. Immunol. 25, 649–679 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Weerkamp, F. et al. Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules. Proc. Natl Acad. Sci. USA 103, 3322–3326 (2006). This study shows that WNT signalling mainly occurs in immature thymocytes (by reporter assays) and that inhibition of WNT signalling leads to a DN1 block in T-cell development. In addition, it was shown that WNT signal transduction is mainly regulated by differential expression of intracellular mediators, not by differential WNT or Frizzled expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Pongracz, J. E., Parnell, S. M., Jones, T., Anderson, G. & Jenkinson, E. J. Overexpression of ICAT highlights a role for catenin-mediated canonical Wnt signalling in early T cell development. Eur. J. Immunol. 36, 2376–2383 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Mulroy, T., Xu, Y. & Sen, J. M. β-catenin expression enhances generation of mature thymocytes. Int. Immunol. 15, 1485–1494 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Gounari, F. et al. Somatic activation of β-catenin bypasses pre-TCR signaling and TCR selection in thymocyte development. Nature Immunol. 2, 863–869 (2001).

    Article  CAS  Google Scholar 

  70. Goux, D. et al. Cooperating pre-T-cell receptor and TCF-1-dependent signals ensure thymocyte survival. Blood 106, 1726–1733 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Xu, Y., Banerjee, D., Huelsken, J., Birchmeier, W. & Sen, J. M. Deletion of β-catenin impairs T cell development. Nature Immunol. 4, 1177–1182 (2003). Conditional deletion of β-catenin in thymocytes using the proximal LCK promoter to drive Cre expression results in abnormal T-cell development, indicating an important role for WNT–β-catenin signalling in T-cell development.

    Article  CAS  Google Scholar 

  72. Ioannidis, V., Beermann, F., Clevers, H. & Held, W. The β-catenin–TCF-1 pathway ensures CD4+CD8+ thymocyte survival. Nature Immunol. 2, 691–697 (2001).

    Article  CAS  Google Scholar 

  73. Gounari, F. et al. Loss of adenomatous polyposis coli gene function disrupts thymic development. Nature Immunol. 6, 800–809 (2005).

    Article  CAS  Google Scholar 

  74. Huang, Z. et al. Transcriptional regulation of CD4 gene expression by T cell factor-1/β -catenin pathway. J. Immunol. 176, 4880–4887 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Yu, Q. & Sen, J. M. β-catenin regulates positive selection of thymocytes but not lineage commitment. J. Immunol. 178, 5028–5034 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Yu, Q., Xu, M. & Sen, J. M. β-catenin expression enhances IL-7 receptor signaling in thymocytes during positive selection. J. Immunol. 179, 126–131 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Terra, R. et al. T-cell generation by lymph node resident progenitor cells. Blood 106, 193–200 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Ranheim, E. A. et al. Frizzled 9 knock-out mice have abnormal B-cell development. Blood 105, 2487–2494 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Dosen, G. et al. Wnt expression and canonical Wnt signaling in human bone marrow B lymphopoiesis. BMC Immunol. 7, 13 (2006).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Willinger, T. et al. Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo. J. Immunol. 176, 1439–1446 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Ding, Y., Shen, S., Lino, A. C., Curotto de Lafaille, M. A. & Lafaille, J. J. β-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nature Med. 14, 162–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Wu, B., Crampton, S. P. & Hughes, C. C. Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity 26, 227–239 (2007). This study shows that endothelial cells are a source of WNT proteins, which subsequently trigger the production of MMP2 and MMP9 by effector T cells and thereby increase their ability to cross the endothelial-cell layer.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Lehtonen, A. et al. Gene expression profiling during differentiation of human monocytes to macrophages or dendritic cells. J. Leukoc. Biol. 82, 710–720 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Blumenthal, A. et al. The Wingless homolog WNT5A and its receptor Frizzled-5 regulate inflammatory responses of human mononuclear cells induced by microbial stimulation. Blood 108, 965–973 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Lobov, I. B. et al. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437, 417–421 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Jiang, A. et al. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27, 610–624 (2007). This study shows that disruption of E-cadherin-mediated adhesion in DCs activates the β-catenin-dependent WNT pathway in DCs, which in turn will elicit a regulatory T-cell response instead of an effector T-cell response. So, active WNT signalling in DCs might contribute to the generation of tolerogenic DCs.

    Google Scholar 

  87. Fodde, R. & Brabletz, T. Wnt/β-catenin signaling in cancer stemness and malignant behavior. Curr. Opin. Cell. Biol. 19, 150–158 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Muller-Tidow, C. et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol. Cell. Biol. 24, 2890–2904 (2004).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Ysebaert, L. et al. Expression of β-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia 20, 1211–1216 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Skokowa, J. et al. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nature Med. 12, 1191–1197 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Jamieson, C. H. et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657–667 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Weerkamp, F., van Dongen, J. J. & Staal, F. J. Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia. Leukemia 20, 1197–1205 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Guo, Z. et al. β-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation. Blood 109, 5463–5472 (2007). The first demonstration that dysregulated WNT signalling in the thymus can cause leukaemia.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Xu, M. et al. β-catenin expression results in p53-independent DNA damage and oncogene-induced senescence in prelymphomagenic thymocytes in vivo. Mol. Cell. Biol. 28, 1713–1723 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Petropoulos, K. et al. A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis. J. Exp. Med. 205, 515–522 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Derksen, P. W. et al. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells. Proc. Natl Acad. Sci. USA 101, 6122–6127 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Giuliani, N. et al. Production of Wnt inhibitors by myeloma cells: potential effects on canonical Wnt pathway in the bone microenvironment. Cancer Res. 67, 7665–7674 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Tian, E. et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med. 349, 2483–2494 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Li, J. et al. CBP/p300 are bimodal regulators of Wnt signaling. EMBO J. 26, 2284–2294 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Townsley, F. M., Cliffe, A. & Bienz, M. Pygopus and Legless target Armadillo/ β-catenin to the nucleus to enable its transcriptional co-activator function. Nature Cell Biol. 6, 626–633 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Weiske, J. & Huber, O. The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF-β-catenin-mediated transcription. J. Cell Sci. 118, 3117–3129 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. McWhirter, J. R. et al. Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia. Proc. Natl Acad. Sci. USA 96, 11464–11469 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Staal, F. J., Burgering, B. M., van de Wetering, M. & Clevers, H. C. Tcf-1-mediated transcription in T lymphocytes: differential role for glycogen synthase kinase-3 in fibroblasts and T cells. Int. Immunol. 11, 317–323 (1999).

    Article  CAS  PubMed  Google Scholar 

  105. Jho, E. H. et al. Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol. Cell. Biol. 22, 1172–1183 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Maretto, S. et al. Mapping Wnt/β-catenin signaling during mouse development and in colorectal tumors. Proc. Natl Acad. Sci. USA 100, 3299–3304 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Moriyama, A. et al. GFP transgenic mice reveal active canonical Wnt signal in neonatal brain and in adult liver and spleen. Genesis 45, 90–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Papkoff, J. & Aikawa, M. WNT-1 and HGF regulate GSK3 βactivity and β-catenin signaling in mammary epithelial cells. Biochem. Biophys. Res. Commun. 247, 851–858 (1998).

    Article  CAS  PubMed  Google Scholar 

  109. van Noort, M., Weerkamp, F., Clevers, H. C. & Staal, F. J. Wnt signaling and phosphorylation status of b-catenin: importance of the correct antibody tools. Blood 110, 2778–2779 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Sansom, O. J. et al. Cyclin D1 is not an immediate target of β-catenin following Apc loss in the intestine. J. Biol. Chem. 280, 28463–28467 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank R. Fodde, A. Langerak and L. Taams for critically reading the manuscript, and N. Restifo and B. Clausen for permission to cite unpublished work. T.C.L. is supported by Fundação para a Ciência e a Tecnologia, Portugal. M.M.T. is supported by the Association for International Cancer Research.

Author information

Authors and Affiliations

  1. Department of Immunology, Erasmus University Medical Center, Rotterdam, 3015 GE, The Netherlands

    Frank J. T. Staal, Tiago C. Luis & Machteld M. Tiemessen

Authors
  1. Frank J. T. Staal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiago C. Luis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Machteld M. Tiemessen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank J. T. Staal.

Related links

Related links

FURTHER INFORMATION

Frank Staal's homepage

Small molecules in Wnt signaling

Glossary

Dorsal axis

Also referred to as the dorsal–ventral axis, this axis establishes the front (ventral) and back (dorsal) of the embryo, resulting in the establishment of polarity.

Asymmetric cell division

A type of division that produces two daughter cells with different properties. This is in contrast to normal cell divisions, which give rise to equivalent daughter cells. Notably, stem cells can divide asymmetrically to give rise to two distinct daughter cells: one copy of themselves and one cell programmed to differentiate into another cell type.

HSC niche

The specialized microenvironment in which haematopoietic stem cells (HSCs) reside. The HSC niche provides signals that regulate self-renewal and differentiation, ensuring homeostasis of the haematopoietic system.

LSK cells

A mouse cell population that is highly enriched in HSCs and defined by the absence of lineage/maturation markers (LIN−), and expression of stem-cell antigen 1 (SCA1) and the receptor for stem-cell factor KIT. This is a heterogeneous population containing multipotent progenitors and true self-renewing stem cells.

Inducible Mx–Cre system

The Cre recombinase gene is under control of the Mx promoter, which can be activated by type I interferons. Administration of a synthetic double-stranded RNA induces the production of interferons and subsequently leads to activation of the Mx promoter. In this way, Cre-mediated deletion of target genes can be induced in specific tissues and at specific developmental stages.

VAV–Cre system

The regulatory sequences of the VAV gene drive pan-haematopoietic-cell expression of the Cre recombinase in adult mice and during embryonic development. The VAV gene encodes a guanine nucleotide-exchange protein, and in addition to the haematopoietic system, expression is also detected in endothelial cells, as well as in testicular germ cells and developing teeth.

Notch signalling pathway

A highly conserved signal-transduction pathway that regulates developmental processes by controlling cell-fate decisions, proliferation and apoposis during embryonic and adult life. Activation of this pathway requires cell–cell contact, between the extracellular domain of Notch and a membrane-bound ligand from a neighbouring cell.

Fetal thymic organ cultures

An in vitro assay for T-cell development in which removal of fetal thymi between embryonic day 14 and 16 allows for the analysis of several key processes in thymic development. The thymic lobes can also be used to allow the development of progenitor cells that are added to the cultures.

Positive and negative selection

T cells that express T-cell receptors with moderate to high affinity for self antigens receive a survival signal and continue to develop towards becoming double positive (CD4+CD8+) T cells. This positive selection occurs through antigens presented by resident stromal cells and dendritic cells in the thymic cortex and is followed by negative selection. Thymocytes expressing T-cell receptors that strongly recognize self peptide bound to self MHC molecules undergo apoptosis in response to the signalling generated by high-affinity binding.

β-selection

The process during T-cell development by which pre-TCR (pre-T-cell receptor) signalling checks for successful rearrangement of TCRB. After successful V(D)J rearrangement, a polymorphic TCR β-chain associates with the non-polymorphic pre-TCR α-chain to form the pre-TCR, which signals proliferation, further differentiation and termination of re-arrangement of the other TCRB allele.

Pro-B cells

Cells in the earliest stage of B-cell development in the bone marrow. They are characterized by incomplete immunoglobulin heavy-chain rearrangements and are defined as CD19+ cytoplasmic IgM.

Pre-B cell

A cell in a stage of B-cell development in the bone marrow that is characterized by complete immunoglobulin heavy-chain rearrangement in the absence of immunoglobulin light-chain rearrangement. Pre-B cells express the pre-B-cell receptor, which comprises a pseudo light chain and a heavy chain.

Myeloid DCs

A subset of CD8α− dendritic cells that might be important for initiating vigorous immune responses.

Plasmacytoid DCs

Immature dendritic cells with a morphology that resembles that of a plasmablast. Plasmacytoid DCs produce large amounts of type I interferons in response to viral infection.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of the human autoimmune disease multiple sclerosis. EAE is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Severe congenital neutropaenia

A genetically heterogeneous disorder of haematopoiesis characterized by a maturation arrest of granulocyte development at the level of promyelocytes with low peripheral blood absolute neutrophil counts, leading to a high susceptibility to infections.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Staal, F., Luis, T. & Tiemessen, M. WNT signalling in the immune system: WNT is spreading its wings. Nat Rev Immunol 8, 581–593 (2008). https://doi.org/10.1038/nri2360

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2360

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing