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.

  • Mini Review
  • Published:

4-1BB signaling beyond T cells

Cellular & Molecular Immunology volume 8, pages 281–284 (2011)Cite this article

Abstract

Originally discovered as a T cell-activating molecule, 4-1BB (CD137) is now also recognized as an activator of non-T cells, thus imparting a new dimension to its potential in vivo effects. 4-1BB expression is seen on a variety of non-T cells including activated dendritic cells (DCs), monocytes, neutrophils, B cells and natural killer (NK) cells, and promotes their individual effector functions. The T cell- and non-T cell-activating ability of 4-1BB may be the basis of its powerful anti-cancer, anti-autoimmune and anti-viral effects. Here we discuss the consequence and importance of 4-1BB signaling in non-T cells. We consider its effects on immune regulation, and the distinct and/or overlapping pathways involved in these responses, as well as possible therapeutic applications.

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

Similar content being viewed by others

References

  1. Kwon BS, Weissman SM . cDNA sequences of two inducible T-cell genes. Proc Natl Acad Sci USA 1989; 86: 1963–1967.

    Article  CAS  Google Scholar 

  2. Watts TH . The TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 2005; 23: 23–68.

    Article  CAS  Google Scholar 

  3. Croft M . Costimulation of T cells by OX-40, 4-1BB, and CD27. Cytokine Growth Factor Rev 2003; 14: 265–273.

    Article  CAS  Google Scholar 

  4. Wilcox RA, Chapoval AI, Gorski KS, Otsuji M, Shin T, Flies DB et al. Expression of functional CD137 receptor by dendritic cells. J Immunol 2002; 168: 4262–4267.

    Article  CAS  Google Scholar 

  5. McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M et al. CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002; 16: 311–323.

    Article  CAS  Google Scholar 

  6. Vinay DS, Kwon BS . Genes, transcripts, and proteins of CD137 receptor and ligand. In: Chen L, ed. CD137 Pathway: Immunology and Diseases. Springer: New York, 2006: 1–14.

    Google Scholar 

  7. Vinay DS, Cha K, Kwon BS . Dual immunoregulatory pathways of 4-1BB signaling. J Mol Med 2006; 84: 726–736.

    Article  CAS  Google Scholar 

  8. Niu L, Strahotin S, Hewes B, Zhang B, Zhang Y, Archer D et al. Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J Immunol 2007; 178: 4194–4213.

    Article  CAS  Google Scholar 

  9. Sun Y, Chen HM, Subudhi SK, Chen J, Koka R, Chen L et al. Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med 2002; 8: 1405–1413.

    Article  CAS  Google Scholar 

  10. Vinay DS, Kim JD, Kwon BS . Amelioration of mercury-induced autoimmunity by 4-1BB. J Immunol 2006; 177: 5708–5717.

    Article  CAS  Google Scholar 

  11. Menoret A, Myers LM, Lee SJ, Mittler RS, Rossi RJ, Vella AT . TGFβ protein processing and activity through TCR triggering of primary CD8+ T regulatory cells. J Immunol 2006; 177: 6091–6097.

    Article  CAS  Google Scholar 

  12. Myers L, Croft M, Kwon BS, Mittler RS, Vella AT . Peptide-specific CD8 T regulatory cells use IFN-γ to elaborate TGF-β-based suppression. J Immunol 2005; 174: 7625–7632.

    Article  CAS  Google Scholar 

  13. Choi BK, Asai T, Vinay DS, Kim YH, Kwon BS . 4-1BB-mediated amelioration of experimental autoimmune uveoretinitis is caused by indoleamine 2,3-dioxygenase-dependent mechanisms. Cytokine 2006; 34: 233–242.

    Article  CAS  Google Scholar 

  14. Seo SK, Choi JH, Kim YH, Kang WJ, Park YH, Suh JH et al. 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat Med 2004; 10: 1088–1094.

    Article  CAS  Google Scholar 

  15. Futagawa T, Akiba H, Kodama T, Takeda K, Hosoda Y, Yagita H et al. Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int Immunol 2002; 14: 275–286.

    Article  CAS  Google Scholar 

  16. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767–811.

    Article  CAS  Google Scholar 

  17. Palucka K, Banchereau J . Dendritic cells: a link between innate and adaptive immunity. J Clin Immunol 1999; 19: 12–25.

    Article  CAS  Google Scholar 

  18. Zhang B, Zhang Y, Niu L, Vella AT, Mittler RS . Dendritic cells and Stat3 are essential for CD137-induced CD8 T cell activation-induced cell death. J Immunol 2010; 184: 4770–4778.

    Article  CAS  Google Scholar 

  19. Lee SW, Park Y, So T, Kwon BS, Cheroutre H, Mittler RS et al. Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells. Nat Immunol 2008; 9: 917–926.

    Article  CAS  Google Scholar 

  20. Choi BK, Kim YH, Kwon PM, Lee SC, Kang SW, Kim MS et al. 4-1BB functions as a survival factor in dendritic cells. J Immunol 2009; 182: 4107–4115.

    Article  CAS  Google Scholar 

  21. Auffray C, Sieweke MH, Geissmann F . Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 2009; 27: 669–692.

    Article  CAS  Google Scholar 

  22. Schwarz H, Valbracht J, Tuckwell J, von Kempis J, Lotz M . ILA, the human 4-1BB homologues, is inducible in lymphoid and other cell lineages. Blood 1995; 85: 1043–1052.

    CAS  PubMed  Google Scholar 

  23. Kienzle G, von Kempis J . CD137 (ILA/4-1BB), expressed by primary human monocytes, induces monocyte activation and apoptosis of B lymphocytes. Int Immunol 2000; 12: 73–82.

    Article  CAS  Google Scholar 

  24. Benschop RJ, Cambier JC . B cell development: signal transduction by antigen receptors and their surrogates. Curr Opin Immunol 1999; 11: 143–151.

    Article  CAS  Google Scholar 

  25. Williams MGH . B cells as effectors. Curr Opin Immunol 2003; 15: 354–361.

    Article  Google Scholar 

  26. Bachmann MF, Zinkernagel RM . Neutralizing anti-viral responses. Annu Rev Immunol 1997; 15: 235–270.

    Article  CAS  Google Scholar 

  27. Edwards JC, Cambridge G . B cell-targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol 2006; 6: 394–402.

    Article  CAS  Google Scholar 

  28. Zhang X, Voskens CJ, Sallin M, Maniar A, Montes CL, Zhang Y et al. CD137 promotes proliferation and survival of human B cells. J Immunol 2010; 184: 787–795.

    Article  CAS  Google Scholar 

  29. Matsukawa A, Yoshinaga M . Neutrophils as a source of cytokines in inflammation. Histol Histopathol 1999; 14: 511–516.

    CAS  PubMed  Google Scholar 

  30. Bliss SK, Marshall AJ, Zhang Y, Denkers EY . Human polymorphonuclear leukocytes produce IL-12, TNF-α, and the chemokines macrophage-inflammatory protein-1α and -1β in response to Toxoplasma gondii antigens. J Immunol 1999; 162: 7369–7375.

    CAS  PubMed  Google Scholar 

  31. Lee SC, Ju SA, Sung BH, Heo SK, Cho HR, Lee EA et al. Stimulation of the molecule 4-1BB enhances host defense against Listeria monocytogenes infection in mice by inducing rapid infiltration and activation of neutrophils and monocytes. Infect Immun 2009; 179: 2168–2176.

    Article  Google Scholar 

  32. Shea-Donohue T, Stiltz J, Zhao A, Notari L . Mast cells. Curr Gastroenterol Rep 2010; 12: 349–357.

    Article  Google Scholar 

  33. Nishimoto H, Lee SW, Hong H, Potter KG, Yamamoto MM, Kinoshita T et al. Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor. Blood 2005; 106: 4241–4248.

    Article  CAS  Google Scholar 

  34. Trinchieri G . Biology of natural killer cells. Adv Immunol 1989; 47: 187–376.

    Article  CAS  Google Scholar 

  35. Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L . NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol 1998; 190: 167–172.

    Article  CAS  Google Scholar 

  36. Vinay DS, Choi BK, Bae JS, Kim WY, Gebhardt BM, Kwon BS . CD137-deficient mice have reduced NK/NKT cell numbers and function, are resistant to lipopolysaccharide-induced shock syndromes, and have lower IL-4 responses. J Immunol 2004; 173: 4218–4229.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Cancer Center, Korea (NCC-0890830-2 and NCC-0810720-2); the Korean Science and Engineering Foundation (Stem Cell-M10641000040 and Discovery of Global New Drug-M10870060009); the Korean Research Foundation (KRF-2005-084-E00001); and Korea Health 21 R&D (A050260).

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Clinical Immunology, Allergy, and Rheumatology, Tulane University Health Sciences Center, New Orleans, LA, USA

    Dass S Vinay & Byoung S Kwon

  2. Cell and Immunobiology, and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Gyeonggi-Do, Korea

    Byoung S Kwon

Authors
  1. Dass S Vinay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Byoung S Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Byoung S Kwon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vinay, D., Kwon, B. 4-1BB signaling beyond T cells. Cell Mol Immunol 8, 281–284 (2011). https://doi.org/10.1038/cmi.2010.82

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2010.82

Keywords

This article is cited by

Search

Advanced search

Quick links