DOI QR코드

DOI QR Code

Is CD137 Ligand (CD137L) Signaling a Fine Tuner of Immune Responses?

  • Received : 2015.02.23
  • Accepted : 2015.06.04
  • Published : 2015.06.30

Abstract

Now, it has been being accepted that reverse signaling through CD137 ligand (CD137L) plays an important role in vivo during hematopoiesis and in immune regulation. However, due to technical difficulty in dissecting both directional signaling events simultaneously in vivo, most biological activities caused by CD137-CD137L interactions are considered as results from signaling events of the CD137 receptor. To make the story more complex, $CD137^{-/-}$ and $CD137L^{-/-}$ mice have increased or decreased immune responses in a context-dependent manner. In this Mini review, I will try to provide a plausible explanation for how CD137L signaling is controlled during immune responses.

Keywords

References

  1. Croft, M. 2009. The role of TNF superfamily members in T-cell function and diseases. Nat. Rev. Immunol. 9: 271-285. https://doi.org/10.1038/nri2526
  2. Shao, Z., and H. Schwarz. 2011. CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. J. Leukoc. Biol. 89: 21-29. https://doi.org/10.1189/jlb.0510315
  3. Kwon, B. 2012. Regulation of inflammation by bidirectional signaling through CD137 and its ligand. Immune Netw 12: 176-180. https://doi.org/10.4110/in.2012.12.5.176
  4. Ho, W. T., W. L. Pang, S. M. Chong, A. Castella, S. Al-Salam, T. E. Tan, M. C. Moh, L. K. Koh, S. U. Gan, C. K. Cheng, and H. Schwarz. 2013. Expression of CD137 on Hodgkin and Reed- Sternberg cells inhibits T-cell activation by eliminating CD137 ligand expression. Cancer Res. 73: 652-661. https://doi.org/10.1158/0008-5472.CAN-12-3849
  5. Eun, S. Y., S. W. Lee, Y. Xu, and M. Croft. 2015. 4-1BB ligand signaling to T cells limits T cell activation. J. Immunol. 194: 134-141. https://doi.org/10.4049/jimmunol.1401383
  6. Quek, B. Z., Y. C. Lim, J. H. Lin, T. E. Tan, J. Chan, A. Biswas, and H. Schwarz. 2010. CD137 enhances monocyte-ICAM-1 interactions in an E-selectin-dependent manner under flow conditions. Mol. Immunol. 47: 1839-1847. https://doi.org/10.1016/j.molimm.2009.11.010
  7. Olofsson, P. S., L. A. Soderstrom, D. Wagsater, Y. Sheikine, P. Ocaya, F. Lang, C. Rabu, L. Chen, M. Rudling, P. Aukrust, U. Hedin, G. Paulsson-Berne, A. Sirsjo, and G. K. Hansson. 2008. CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 117: 1292-1301. https://doi.org/10.1161/CIRCULATIONAHA.107.699173
  8. Jeon, H. J., J. H. Choi, I. H. Jung, J. G. Park, M. R. Lee, M. N. Lee, B. Kim, J. Y. Yoo, S. J. Jeong, D. Y. Kim, J. E. Park, H. Y. Park, K. Kwack, B. K. Choi, B. S. Kwon, and G. T. Oh. 2010. CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice. Circulation 121: 1124-1133. https://doi.org/10.1161/CIRCULATIONAHA.109.882704
  9. Kim, H. J., J. S. Lee, J. D. Kim, H. J. Cha, A. Kim, S. K. Lee, S. C. Lee, B. S. Kwon, R. S. Mittler, H. R. Cho, and B. Kwon. 2012. Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation. Proc. Natl. Acad. Sci. U. S. A. 109: E13-E22. https://doi.org/10.1073/pnas.1112256109
  10. Kim, H. J., J. S. Lee, A. Kim, S. Koo, H. J. Cha, J. A. Han, Y. Do, K. M. Kim, B. S. Kwon, R. S. Mittler, H. R. Cho, and B. Kwon. 2013. TLR2 signaling in tubular epithelial cells regulates NK cell recruitment in kidney ischemia-reperfusion injury. J. Immunol. 191: 2657-2664. https://doi.org/10.4049/jimmunol.1300358
  11. Fontana, M. F., and R. E. Vance. 2011. Two signal models in innate immunity. Immunol. Rev. 243: 26-39. https://doi.org/10.1111/j.1600-065X.2011.01037.x
  12. Tang, Q., D. Jiang, S. Alonso, A. Pant, J. M. Martinez Gomez, D. M. Kemeny, L. Chen, and H. Schwarz. 2013. CD137 ligand signaling enhances myelopoiesis during infections. Eur. J. Immunol. 43: 1555-1567. https://doi.org/10.1002/eji.201243071
  13. Lee, S. W., Y. Park, T. So, B. S. Kwon, H. Cheroutre, R. S. Mittler, and M. Croft. 2008. Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells. Nat. Immunol. 9: 917-926.
  14. Zhu, G., D. B. Flies, K. Tamada, Y. Sun, M. Rodriguez, Y. X. Fu, and L. Chen. 2001. Progressive depletion of peripheral B lymphocytes in 4-1BB (CD137) ligand/I-Ealpha)-transgenic mice. J. Immunol. 167: 2671-2676. https://doi.org/10.4049/jimmunol.167.5.2671
  15. Jiang, D., Y. Chen, and H. Schwarz. 2008. CD137 induces proliferation of murine hematopoietic progenitor cells and differentiation to macrophages. J. Immunol. 181: 3923-3932. https://doi.org/10.4049/jimmunol.181.6.3923
  16. Jiang, D., P. S. Yue, D. Drenkard, and H. Schwarz. 2008. Induction of proliferation and monocytic differentiation of human CD34+ cells by CD137 ligand signaling. Stem Cells 26: 2372-2381. https://doi.org/10.1634/stemcells.2008-0158
  17. Kang, Y. J., S. O. Kim, S. Shimada, M. Otsuka, A. Seit-Nebi, B. S. Kwon, T. H. Watts, and J. Han. 2007. Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages. Nat. Immunol. 8: 601-609.
  18. Kwon, B. S., J. C. Hurtado, Z. H. Lee, K. B. Kwack, S. K. Seo, B. K. Choi, B. H. Koller, G. Wolisi, H. E. Broxmeyer, and D. S. Vinay. 2002. Immune responses in 4-1BB (CD137)-deficient mice. J. Immunol. 168: 5483-5490. https://doi.org/10.4049/jimmunol.168.11.5483
  19. Lee, S. W., A. T. Vella, B. S. Kwon, and M. Croft. 2005. Enhanced CD4 T cell responsiveness in the absence of 4-1BB. J. Immunol. 174: 6803-6808. https://doi.org/10.4049/jimmunol.174.11.6803
  20. Martinez Gomez, J. M., L. Chen, H. Schwarz, and T. Karrasch. 2013. CD137 facilitates the resolution of acute DSS-induced colonic inflammation in mice. PLoS One 8: e73277. https://doi.org/10.1371/journal.pone.0073277

Cited by

  1. CD137‐CRDI is not necessary in the role of contacting its natural ligand vol.95, pp.1, 2017, https://doi.org/10.1038/icb.2016.64
  2. CD137+CD154− Expression As a Regulatory T Cell (Treg)-Specific Activation Signature for Identification and Sorting of Stable Human Tregs from In Vitro Expansion Cultures vol.9, pp.None, 2015, https://doi.org/10.3389/fimmu.2018.00199
  3. CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8+ T Cell–Relevant Genes vol.6, pp.1, 2015, https://doi.org/10.1158/2326-6066.cir-17-0159
  4. White Adipose Tissue Response of Obese Mice to Ambient Oxygen Restriction at Thermoneutrality: Response Markers Identified, but no WAT Inflammation vol.10, pp.5, 2015, https://doi.org/10.3390/genes10050359
  5. High Level Expression of MHC-II in HPV+ Head and Neck Cancers Suggests that Tumor Epithelial Cells Serve an Important Role as Accessory Antigen Presenting Cells vol.11, pp.8, 2015, https://doi.org/10.3390/cancers11081129
  6. Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition vol.7, pp.1, 2019, https://doi.org/10.1186/s40425-019-0758-y
  7. Immunotherapeutic Targets and Therapy for Renal Cell Carcinoma vol.9, pp.None, 2020, https://doi.org/10.2147/itt.s240889
  8. Immune induction identified by TMT proteomics analysis in Fusobacterium nucleatum autoinducer-2 treated macrophages vol.17, pp.2, 2015, https://doi.org/10.1080/14789450.2020.1738223
  9. Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity vol.5, pp.5, 2015, https://doi.org/10.1172/jci.insight.133647
  10. CD137 Signaling Is Critical in Fungal Clearance during Systemic Candida albicans Infection vol.7, pp.5, 2015, https://doi.org/10.3390/jof7050382