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The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function

Nature Immunology volume 7, pages 851–858 (2006)Cite this article

Abstract

The kinase TAK1 is critical for innate and B cell immunity. The function of TAK1 in T cells is unclear, however. We show here that T cell–specific deletion of the gene encoding TAK1 resulted in reduced development of thymocytes, especially of regulatory T cells expressing the transcription factor Foxp3. In mature thymocytes, TAK1 was required for interleukin 7–mediated survival and T cell receptor–dependent activation of transcription factor NF-κB and the kinase Jnk. In effector T cells, TAK1 was dispensable for T cell receptor–dependent NF-κB activation and cytokine production, but was important for proliferation and activation of the kinase p38 in response to interleukins 2, 7 and 15. Thus, TAK1 is essential for the integration of T cell receptor and cytokine signals to regulate the development, survival and function of T cells.

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Figure 1: TAK1 is required for T cell development.
Figure 2: Ablated thymic development of nTreg cells contributes to the activated phenotype of peripheral T cells in Map3k7Cre/− mice.
Figure 3: IL-7-mediated T cell survival depends on TAK1.
Figure 4: TAK1 is required for TCR-mediated cellular responses and NF-κB and Jnk activation in mature thymocytes.
Figure 5: TAK1, which is required for Jnk activation, is dispensable for TCR-induced cytokine production and NF-κB activation in effector T cells.
Figure 6: TAK1 is essential for the survival and cytokine-driven proliferation of effector T cells.
Figure 7: TAK1 is essential for IL-2-, IL-7- and IL-15-mediated p38 activation in effector T cells.

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References

  1. Dong, C., Davis, R.J. & Flavell, R.A. MAP kinases in immune response. Annu. Rev. Immunol. 20, 55–72 (2002).

    Article  CAS  Google Scholar 

  2. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).

    Article  CAS  Google Scholar 

  3. Kyriakis, J.M. & Avruch, J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807–869 (2001).

    Article  CAS  Google Scholar 

  4. Huang, Q. et al. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat. Immunol. 5, 98–103 (2004).

    Article  CAS  Google Scholar 

  5. Shim, J.H. et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev. 19, 2668–2681 (2005).

    Article  CAS  Google Scholar 

  6. Sato, S. et al. Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat. Immunol. 6, 1087–1095 (2005).

    Article  CAS  Google Scholar 

  7. Ninomiya-Tsuji, J. et al. The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398, 252–256 (1999).

    Article  CAS  Google Scholar 

  8. Takaesu, G. et al. TAK1 is critical for IκB kinase-mediated activation of the NF-κB pathway. J. Mol. Biol. 326, 105–115 (2003).

    Article  CAS  Google Scholar 

  9. Yang, J. et al. The essential role of MEKK3 in TNF-induced NF-κB activation. Nat. Immunol. 2, 620–624 (2001).

    Article  CAS  Google Scholar 

  10. Vidal, S. et al. Mutations in the Drosophila dTAK1 gene reveal a conserved function for MAPKKKs in the control of rel/NF-κB-dependent innate immune responses. Genes Dev. 15, 1900–1912 (2001).

    Article  CAS  Google Scholar 

  11. Shinohara, H. et al. PKCβ regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J. Exp. Med. 202, 1423–1431 (2005).

    Article  CAS  Google Scholar 

  12. Sun, L., Deng, L., Ea, C.-K., Xia, Z.-P. & Chen, Z.J. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell 14, 289–301 (2004).

    Article  CAS  Google Scholar 

  13. Ruland, J. & Mak, T.W. Transducing signals from antigen receptors to nuclear factor κB. Immunol. Rev. 193, 93–100 (2003).

    Article  CAS  Google Scholar 

  14. Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nat. Rev. Immunol. 4, 348–359 (2004).

    Article  CAS  Google Scholar 

  15. Weil, R. & Israel, A. T-cell-receptor- and B-cell-receptor-mediated activation of NF-κB in lymphocytes. Curr. Opin. Immunol. 16, 374–381 (2004).

    Article  CAS  Google Scholar 

  16. Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nat. Immunol. 3, 221–227 (2002).

    Article  CAS  Google Scholar 

  17. Siebenlist, U., Brown, K. & Claudio, E. Control of lymphocyte development by nuclear factor-κB. Nat. Rev. Immunol. 5, 435–445 (2005).

    Article  CAS  Google Scholar 

  18. Lee, P.P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).

    Article  CAS  Google Scholar 

  19. Sen, J. et al. Expression and induction of nuclear factor-κB-related proteins in thymocytes. J. Immunol. 154, 3213–3221 (1995).

    CAS  Google Scholar 

  20. Sabapathy, K. et al. c-Jun NH2-terminal kinase (JNK)1 and JNK2 have similar and stage-dependent roles in regulating T cell apoptosis and proliferation. J. Exp. Med. 193, 317–328 (2001).

    Article  CAS  Google Scholar 

  21. Schmidt-Supprian, M. et al. Mature T cells depend on signaling through the IKK complex. Immunity 19, 377–389 (2003).

    Article  CAS  Google Scholar 

  22. Pasparakis, M., Schmidt-Supprian, M. & Rajewsky, K. IκB kinase signaling Is essential for maintenance of mature B cells. J. Exp. Med. 196, 743–752 (2002).

    Article  CAS  Google Scholar 

  23. Rincon, M. et al. The JNK pathway regulates the in vivo deletion of immature CD4+CD8+ thymocytes. J. Exp. Med. 188, 1817–1830 (1998).

    Article  CAS  Google Scholar 

  24. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

    Article  CAS  Google Scholar 

  25. Fontenot, J.D. & Rudensky, A.Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6, 331–337 (2005).

    Article  CAS  Google Scholar 

  26. Fry, T.J. & Mackall, C.L. The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J. Immunol. 174, 6571–6576 (2005).

    Article  CAS  Google Scholar 

  27. Ruland, J. & Mak, T.W. From antigen to activation: specific signal transduction pathways linking antigen receptors to NF-κB. Semin. Immunol. 15, 177–183 (2003).

    Article  CAS  Google Scholar 

  28. Vella, A.T., Dow, S., Potter, T.A., Kappler, J. & Marrack, P. Cytokine-induced survival of activated T cells in vitro and in vivo. Proc. Natl. Acad. Sci. USA 95, 3810–3815 (1998).

    Article  CAS  Google Scholar 

  29. Schluns, K.S. & Lefrancois, L. Cytokine control of memory T-cell development and survival. Nat. Rev. Immunol. 3, 269–279 (2003).

    Article  CAS  Google Scholar 

  30. Kovanen, P.E. & Leonard, W.J. Cytokines and immunodeficiency diseases: critical roles of the γc-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol. Rev. 202, 67–83 (2004).

    Article  CAS  Google Scholar 

  31. Sears, R.C. & Nevins, J.R. Signaling networks that link cell proliferation and cell fate. J. Biol. Chem. 277, 11617–11620 (2002).

    Article  CAS  Google Scholar 

  32. Sherr, C.J. & Roberts, J.M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    Article  CAS  Google Scholar 

  33. DeGregori, J. The Rb network. J. Cell Sci. 117, 3411–3413 (2004).

    Article  CAS  Google Scholar 

  34. Crawley, J.B. et al. T cell proliferation in response to interleukins 2 and 7 requires p38MAP kinase activation. J. Biol. Chem. 272, 15023–15027 (1997).

    Article  CAS  Google Scholar 

  35. Geginat, J., Sallusto, F. & Lanzavecchia, A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4+ T cells. J. Exp. Med. 194, 1711–1719 (2001).

    Article  CAS  Google Scholar 

  36. Sen, J. et al. Intrathymic signals in thymocytes are mediated by p38 mitogen-activated protein kinase. J. Immunol. 156, 4535–4538 (1996).

    CAS  Google Scholar 

  37. Schmidt-Supprian, M. et al. Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-κB activation. Proc. Natl. Acad. Sci. USA 101, 4566–4571 (2004).

    Article  CAS  Google Scholar 

  38. Fontenot, J.D., Rasmussen, J.P., Gavin, M.A. & Rudensky, A.Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C.B. Wilson for CD4-Cre–transgenic mice, E. Eynon for discussions and F. Manzo for secretarial assistance. Supported by the National Institutes of Health (R.A.F.), the Howard Hughes Medical Institute (R.A.F.), the Cancer Research Institute (Y.Y.W.), the Arthritis National Research Foundation (H.C.) and the Charles H. Hood Foundation (H.C.).

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Author notes

  1. Yisong Y Wan and Hongbo Chi: These authors contributed equally to this work.

Authors and Affiliations

  1. Section of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Yisong Y Wan, Hongbo Chi & Richard A Flavell

  2. Center for Cardiovascular Development and Department of Medicine, Baylor College of Medicine, Houston, 77030, Texas, USA

    Min Xie & Michael D Schneider

  3. Howard Hughes Medical Institute, New Haven, 06520, Connecticut, USA

    Richard A Flavell

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  1. Yisong Y Wan
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Correspondence to Richard A Flavell.

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Supplementary information

Supplementary Fig. 1

Phenotypic analysis of DP and CD4 SP thymocytes. (PDF 98 kb)

Supplementary Fig. 2

Surface expression of IL-7Rα is not altered on TAK1 deficient cells. (PDF 24 kb)

Supplementary Fig. 3

TAK1 deficiency results in accelerated T cell apoptosis in the long-term culture. (PDF 34 kb)

Supplementary Fig. 4

TAK1-deficient effector T cells compete poorly with wild-type counterparts in response to cytokine stimulation. (PDF 378 kb)

Supplementary Fig. 5

The numbers of cells recovered at the end of [3H]thymidine incorporation are comparable between TAK1 intact and deficient effector T cells. (PDF 367 kb)

Supplementary Fig. 6

TAK1 deletion did not affect the expression of CD25, IL-7Rα or IL-15Rα on effector T cells. (PDF 29 kb)

Supplementary Fig. 7

TAK1 is essential for the constitutive p38 activity in thymocytes. (PDF 85 kb)

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Wan, Y., Chi, H., Xie, M. et al. The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function. Nat Immunol 7, 851–858 (2006). https://doi.org/10.1038/ni1355

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