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Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells

Abstract

Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways1. The Wnt–β-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation2,3, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt–β-catenin signaling by inhibitors of glycogen sythase kinase-3β or the Wnt protein family member Wnt3a arrested CD8+ T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44lowCD62LhighSca-1highCD122highBcl-2high self-renewing multipotent CD8+ memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8+ T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.

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Figure 1: TWS119 activates Wnt signaling in CD8+ T cells.
Figure 2: Wnt signaling inhibits CD8+ T cell proliferation and effector differentiation.
Figure 3: Wnt signaling promotes the generation of TSCM cells.
Figure 4: TSCM cells possess enhanced in vivo recall response and antitumor activity compared to TCM cells and TEM cells.

References

  1. 1

    Luckey, C.J. et al. Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 103, 3304–3309 (2006).

    CAS  Article  Google Scholar 

  2. 2

    Staal, F.J., Luis, T.C. & Tiemessen, M.M. WNT signalling in the immune system: WNT is spreading its wings. Nat. Rev. Immunol. 8, 581–593 (2008).

    CAS  Article  Google Scholar 

  3. 3

    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).

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Jeannet, G. et al. Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142–149 (2008).

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  PubMed  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    Hinrichs, C.S. et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111, 5326–5333 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Williams, M.A., Ravkov, E.V. & Bevan, M.J. Rapid culling of the CD4+ T cell repertoire in the transition from effector to memory. Immunity 28, 533–545 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Ding, S. et al. Synthetic small molecules that control stem cell fate. Proc. Natl. Acad. Sci. USA 100, 7632–7637 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Roose, J. et al. Synergy between tumor suppressor APC and the β-catenin-Tcf4 target Tcf1. Science 285, 1923–1926 (1999).

    CAS  Article  Google Scholar 

  12. 12

    Hovanes, K et al. β-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. Nat. Genet. 28, 53–57 (2001).

    CAS  PubMed  Google Scholar 

  13. 13

    Mann, B. et al. Target genes of β-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc. Natl. Acad. Sci. USA 96, 1603–1608 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Katoh, M. & Katoh, M. Comparative integromics on FZD7 orthologs: conserved binding sites for PU.1, SP1, CCAAT-box and TCF/LEF/SOX transcription factors within 5′-promoter region of mammalian FZD7 orthologs. Int. J. Mol. Med. 19, 529–533 (2007).

    CAS  PubMed  Google Scholar 

  15. 15

    Zeng, Y.A. & Verheyen, E.M. Nemo is an inducible antagonist of Wingless signaling during Drosophila wing development. Development 131, 2911–2920 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Overwijk, W.W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Gattinoni, L. et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J. Clin. Invest. 115, 1616–1626 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A.H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3–specific inhibitor. Nat. Med. 10, 55–63 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Meijer, L., Flajolet, M. & Greengard, P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol. Sci. 25, 471–480 (2004).

    CAS  Article  Google Scholar 

  20. 20

    Ohteki, T. et al. Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3. J. Exp. Med. 192, 99–104 (2000).

    CAS  Article  Google Scholar 

  21. 21

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

    CAS  Article  Google Scholar 

  22. 22

    Pantaleo, G. & Harari, A. Functional signatures in antiviral T-cell immunity for monitoring virus-associated diseases. Nat. Rev. Immunol. 6, 417–423 (2006).

    CAS  Article  Google Scholar 

  23. 23

    Pearce, E.L. et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302, 1041–1043 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Appay, V., Douek, D.C. & Price, D.A. CD8+ T cell efficacy in vaccination and disease. Nat. Med. 14, 623–628 (2008).

    CAS  Article  Google Scholar 

  25. 25

    Zhang, Y., Joe, G., Hexner, E., Zhu, J. & Emerson, S.G. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat. Med. 11, 1299–1305 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).

    CAS  Article  Google Scholar 

  27. 27

    Kaech, S.M. & Wherry, E.J. Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity 27, 393–405 (2007).

    CAS  Article  Google Scholar 

  28. 28

    Klebanoff, C.A., Gattinoni, L. & Restifo, N.P. CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214–224 (2006).

    CAS  Article  Google Scholar 

  29. 29

    Tough, D.F. & Sprent, J. Turnover of naive- and memory-phenotype T cells. J. Exp. Med. 179, 1127–1135 (1994).

    CAS  Article  Google Scholar 

  30. 30

    Surh, C.D. & Sprent, J. Homeostatic T cell proliferation: how far can T cells be activated to self-ligands? J. Exp. Med. 192, F9–F14 (2000).

    CAS  Article  Google Scholar 

  31. 31

    Murali-Krishna, K. et al. Persistence of memory CD8 T cells in MHC class I–deficient mice. Science 286, 1377–1381 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Wrzesinski, C. et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J. Clin. Invest. 117, 492–501 (2007).

    CAS  Article  Google Scholar 

  33. 33

    Klebanoff, C.A. et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl. Acad. Sci. USA 102, 9571–9576 (2005).

    CAS  Article  Google Scholar 

  34. 34

    Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).

    CAS  Article  Google Scholar 

  35. 35

    Gattinoni, L., Powell, D.J. Jr., Rosenberg, S.A. & Restifo, N.P. Adoptive immunotherapy for cancer: building on success. Nat. Rev. Immunol. 6, 383–393 (2006).

    CAS  Article  Google Scholar 

  36. 36

    Morgan, R.A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

    CAS  Article  Google Scholar 

  37. 37

    Fearon, D.T., Manders, P. & Wagner, S.D. Arrested differentiation, the self-renewing memory lymphocyte and vaccination. Science 293, 248–250 (2001).

    CAS  Article  Google Scholar 

  38. 38

    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. Nat. Med. 14, 162–169 (2008).

    CAS  Article  Google Scholar 

  39. 39

    Chang, J.T. et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315, 1687–1691 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Mizumoto, K. & Sawa, H. Two βs or not two βs: regulation of asymmetric division by β-catenin. Trends Cell Biol. 17, 465–473 (2007).

    CAS  Article  Google Scholar 

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Acknowledgements

This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. We would like to thank S.A. Rosenberg, C.A. Klebanoff and S. Kerkar for critical review of the manuscript and A. Mixon and S. Farid of the Flow Cytometry Unit for Flow Cytometry analyses and sorting. This study was done in partial fulfillment of a PhD in Biochemistry (to D.C.P.) at the George Washington University, Washington, DC.

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L.G. designed, performed and analyzed experiments and wrote the paper; X.-S.Z. D.C.P., Y.J., C.S.H., Z.Y., C.W., A.B., L.C., L.M.G., C.M.P. and P.M. performed experiments; and N.P.R. designed experiments and wrote the paper.

Corresponding authors

Correspondence to Luca Gattinoni or Nicholas P Restifo.

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Gattinoni, L., Zhong, XS., Palmer, D. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 15, 808–813 (2009). https://doi.org/10.1038/nm.1982

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