Role of TRAF6 in the Immune System

  • Yongwon Choi
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 560)


TRAF6 is a member of the TNF receptor associated factor (TRAF) family, members of which are important for signaling induced by a variety of the TNF receptor family members. TRAF6 was initially identified as a signaling adapter for CD40, but has subsequently been shown to be a critical factor for the interleukin-1 receptor~Toll-like receptor (IL-lR/TLR) family. Therefore, TRAF6 represents a central point of con- vergence for the signal transduction by the TNFR and the IL-lR/TLR superfamilies, and thus plays a critical role in the regulation of innate immune responses. Considering the importance of the TNFR and IL-RITLR family members to the regulation of the innate immune system, the extent to which TRAF6 regulates the physiology of innate immunity, as well as the connection between the innate and adaptive immune responses, is of great interest. Here we have described the potential role of TRAF6 in regulating dendritic cell fates.


Tumor Necrosis Factor Receptor Tumor Necrosis Factor Receptor Superfamily Cell Stimulatory Capacity Tumor Necrosis Factor Family Member Tumor Necrosis Factor Receptor Signaling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    C. A. Smith, T. Farrah & R. G. Goodwin. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 76, 959–962 (1994).PubMedCrossRefGoogle Scholar
  2. 2.
    R. M. Locksley, N. Killeen & M. J. Lenardo. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501. (2001).PubMedCrossRefGoogle Scholar
  3. 3.
    D. K. Miller. The role of the caspase family of cysteine proteases in apoptosis. Semin. Immunol. 9, 35–49 (1997).PubMedCrossRefGoogle Scholar
  4. 4.
    M. J. May & S. Ghosh. Signal transduction through NF-kappa B. Immunol Today 19, 80–8 (1998).PubMedCrossRefGoogle Scholar
  5. 5.
    S. Ghosh & M. Karin. Missing pieces in the NF-kappaB puzzle. Cell 109Suppl, S81–96 (2002).PubMedCrossRefGoogle Scholar
  6. 6.
    M. Karin. The regulation of AP-1 activity by mitogen-activated protein kinases. J. Biol. Chem. 270, 16483–16486 (1995).PubMedGoogle Scholar
  7. 7.
    Z. Xia, M. Dickens, J. Raingeaud, R. J. Davis & M. E. Greenberg. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 1326–1331 (1995).PubMedCrossRefGoogle Scholar
  8. 8.
    L. A. Tartaglia, T. M. Ayres, G. H. W. Wong & D. V. Goeddel. A novel domian within the 55 kd TNF receptor signals cell death. Cell 74, 845–853 (1993).PubMedCrossRefGoogle Scholar
  9. 9.
    N. Itoh & S. Nagata. A novel protein domain required for apoptosis. J. Biol. Chem. 268, 10932–10937 (1993).PubMedGoogle Scholar
  10. 10.
    S. Nagata. Apoptosis by Death Factor. Cell 88, 355–365 (1997).PubMedCrossRefGoogle Scholar
  11. 11.
    M. Rothe, S. C. Wong, W. J. Henzel & D. V. Goeddel. A novel family of putative signal transducers associted with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78, 681–692 (1994).PubMedCrossRefGoogle Scholar
  12. 12.
    G. Cheng et al. Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science 267, 1494–1498 (1995).PubMedCrossRefGoogle Scholar
  13. 13.
    H. Nakano et al. TRAF5, an activator of NF-kB and putative signal transducer for the lymphotoxin-beta receptor. J. Biol. Chem. 271, 14661–14664 (1996).PubMedCrossRefGoogle Scholar
  14. 14.
    Z. Cao, J. Xiong, M. Takeuchi, T. Kurama & D. V. Goeddel. TRAF6 is a signal transducer for interleukin-l. Nature 383, 443–446 (1996).PubMedCrossRefGoogle Scholar
  15. 15.
    N. L. Malinin, M. P. Boldin, A. V. Kovalenko & D. Wallach. MAP3K-related kinase involved in NF-kB induction by TNF, CD95 and IL-1. Nature 385, 540–544 (1997).PubMedCrossRefGoogle Scholar
  16. 16.
    E. Zandi, D. M. Rothwarf, M. Delhase, M. Hayakawa & M. Karin. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91, 243–52 (1997).PubMedCrossRefGoogle Scholar
  17. 17.
    J. A. DiDonato, M. Hayakawa, D. M. Rothwarf, E. Zandi & M. Karin. A cytokine-responsive IkB kinase that activates the transcription factor NF-kB. Nature 388, 548–554 (1997).PubMedCrossRefGoogle Scholar
  18. 18.
    J. Y. Chung, Y. C. Park, H. Ye & H. Wu. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci 115, 679–88 (2002).PubMedGoogle Scholar
  19. 19.
    S. Y. Lee et al. TRAF2 is essential for JNK but not NF-kB activation and regulates lymphocyte proliferation and survival. Immunity 7, 703–713. (1997).PubMedCrossRefGoogle Scholar
  20. 20.
    W.-C. Yeh et al. Early lethality, functional NF-kB activation and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7, 715–725 (1997).PubMedCrossRefGoogle Scholar
  21. 21.
    E. N. Tsitsikov et al. TRAF1 is a negative regulator of TNF signaling enhanced TNF signaling in TRAF1-deficient mice. Immunity 15, 647–57 (2001).PubMedCrossRefGoogle Scholar
  22. 22.
    Y. Xu, G. Cheng & D. Baltimore. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity 5, 407–415 (1996).PubMedCrossRefGoogle Scholar
  23. 23.
    A. Naito et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4, 353–362 (1999).PubMedCrossRefGoogle Scholar
  24. 24.
    M. A. Lomaga et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13, 1015–1024 (1999).PubMedGoogle Scholar
  25. 25.
    J. Banchereau & R. M. Steinman. Dendritic cells and the control of immunity. Nature 392, 245–52 (1998).PubMedCrossRefGoogle Scholar
  26. 26.
    R. M. Steinman & M. C. Nussenzweig. Avoiding horror autoloxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 99, 351–8. (2002).PubMedCrossRefGoogle Scholar
  27. 27.
    K. Shortman & Y. J. Liu. Mouse and human dendritic cell subtypes. Nat Rev Immunol 2, 151–61. (2002).PubMedCrossRefGoogle Scholar
  28. 28.
    L. Flores-Romo et al. CD40 ligation on human cord blood CD34+ hematopoietic progenitors induces their proliferation and differentiation into functional dendritic cells. J Exp Med 185, 341–9 (1997).PubMedCrossRefGoogle Scholar
  29. 29.
    C. Caux et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha. J Exp Med 184, 695–706 (1996).PubMedCrossRefGoogle Scholar
  30. 30.
    J. W. Young, P. Szabolcs & M. A. Moore. Identification of dendritic cell colony-forming units among normal human CD34+ bone marrow progenitors that are expanded by c-kit-ligand and yield pure dendritic cell colonies in the presence of granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha. J Exp Med 182, 1111–9 (1995).PubMedCrossRefGoogle Scholar
  31. 31.
    R. J. Noelle. CD40 and its ligand in host defense. Immunity 4, 415–419 (1996).PubMedCrossRefGoogle Scholar
  32. 32.
    J. P. Ridge, F. DiRosa & P. Matzinger. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).PubMedCrossRefGoogle Scholar
  33. 33.
    R. Josien et al. TRANCe, a TNF family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J. Exp. Med. 191, 495–502 (2000).PubMedCrossRefGoogle Scholar
  34. 34.
    M. F. Bachmann et al. TRANCE, a tumor necrosis factor family member critical for CD40 ligand-independent T helper cell activation. J. Exp. Med. 189, 1025–1031 (1999).PubMedCrossRefGoogle Scholar
  35. 35.
    B. R. Wong, R. Josien & Y. Choi. TRANCE is a TNF family member that regulates dendritic cell and osteoclast function. J. Leuk. Biol. 65, 715–724 (1999).Google Scholar
  36. 36.
    C. Van Kooten & J. Bancherean. CD40-CD40 ligand: a multifunctional receptor-ligand pair. Adv. Immunol. 61, 1–77 (1996).PubMedCrossRefGoogle Scholar
  37. 37.
    C. van Kooten & J. Bancherean. Functions of CD40 on B cells, dendritic cells and other cells. Curr Opin Immunol 9, 330–7 (1997).PubMedCrossRefGoogle Scholar
  38. 38.
    B. R. Wong et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinases in T cells. J. Biol. Chem. 272, 25910–25914 (1997).Google Scholar
  39. 39.
    B. R. Wong et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med 186, 2075–80 (1997).PubMedCrossRefGoogle Scholar
  40. 40.
    E. A. Green, Y. Choi & R. A. Flavell. Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity 16, 183–91. (2002).PubMedCrossRefGoogle Scholar
  41. 41.
    L. E. Theill, W. J. Boyle & J. M. Penninger. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 20, 795–823 (2002).PubMedCrossRefGoogle Scholar
  42. 42.
    B. R. Wong et al. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J. Biol. Chem. 273, 28355–28359 (1998).PubMedCrossRefGoogle Scholar
  43. 43.
    B. G. Damay, J. Ni, P. A. Moore & B. B. Aggarwal. Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. J Biol Chem 274, 7724–31 (1999).CrossRefGoogle Scholar
  44. 44.
    L. Galibert, M. E. Tometsko, D. M. Anderson, D. Cosman & W. C. Dougall. The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J Biol Chem 273, 34120–7 (1998).PubMedCrossRefGoogle Scholar
  45. 45.
    D. Kim et al. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J Exp Med 192, 1467–78. (2002).CrossRefGoogle Scholar
  46. 46.
    N. S. Kim, P. R. Odgre, D. K. Kim, J. Marks, S. C. & Y. Choi. Diverse roles of the tumor necrosis factor family member TRANCE in skeleton physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc. Natl. Acad. Sci. USA 97, 10905–10910 (2000).PubMedCrossRefGoogle Scholar
  47. 47.
    Y. Y. Kong et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 397, 315–323 (1999).PubMedCrossRefGoogle Scholar
  48. 48.
    W. C. Dougall et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412–2424 (1999).PubMedCrossRefGoogle Scholar
  49. 49.
    J. Li et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A 97, 1566–71. (2000).PubMedCrossRefGoogle Scholar
  50. 50.
    H. Nakano et al. Targeted disruption of Traf5 gene causes defects in CD40-and CD27-mediated lymphocyte activation. Proc Natl Acad Sci U S A 96, 9803–8 (1999).PubMedCrossRefGoogle Scholar
  51. 51.
    R. Medzhitov et al. MyD88 is an adaptor protein in the h Toll/IL-1 receptor family signaling pathways. Mol Cell 2, 253–8 (1998).PubMedCrossRefGoogle Scholar
  52. 52.
    R. Medzhitov & C. Janeway, Jr. The Toll receptor family and microbial recognition. Trends Microbiol 8, 452–6. (2000).PubMedCrossRefGoogle Scholar
  53. 53.
    S. Akira, K. Takeda & T. Kaisho. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2, 675–80. (2001).PubMedCrossRefGoogle Scholar
  54. 54.
    H. Ye et al. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418, 443–7. (2002).PubMedCrossRefGoogle Scholar
  55. 55.
    T. De Smedt et al. Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J Exp Med 184, 1413–24. (1996).PubMedCrossRefGoogle Scholar
  56. 56.
    T. Kaisho, O. Takeuchi, T. Kawai, K. Hoshino & S. Akira. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J Immunol 166, 5688–94. (2001).PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Yongwon Choi
    • 1
  1. 1.Abramson Family Cancer Research Institute, Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphia

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