Advertisement

CD137 Signal Transduction

  • Hyeon-Woo Lee
  • Byoung S. Kwon

Abstract

T lymphocytes have critical roles in clearing cells expressing foreign antigens. The proliferation of T cells and their differentiation into effector and memory cells confers T cell-mediated adaptive immunity (Abbas et al., 1997). To undertake these antigen-specific functions, T cells require two signals: ligation of the T cell receptor (TCR) by the MHC/peptide complex on the antigen presenting cell (APC), and cross-linking of co-stimulatory receptors on the T cell with corresponding ligands on the APC (Carreno and Collins, 2002; Chambers and Allison, 1999). In addition, cytokines synthesized and released by the APC can modulate T cell functions in a paracrine way (Beginat et al., 2003; Kanegane and Tosato 1996; Lantz et al., 2000; Lodolce et al., 1998; Nakajima et al., 1997; Schluns et al., 2000; Unutmaz et al., 1994; Unutmaz et al., 1995; Zhang et al., 1998). Although the exact mechanisms by which several co-stimulatory molecules can interact to stimulate T cells remain to be uncovered, co-stimulation appears to be an accurate process that subtly evokes T cell immunity (Rothstein and Sayegh, 2003; Samia and Mohamed, 2004; Van Parijs, and Abbas, 1998). Co-stimulatory signals determine whether antigen-priming T cells become fully activated or antigen-specifically inactivated (Samia and Mohamed, 2004). If the concentration of antigen or its affinity for TCR is low, co-stimulatory signals tend to enhance antigen-specific TCR signals and fully activate T cells by activating their own signaling pathways or enhancing those generated by the TCR (Gravestein et al., 1998; Kenneth and Thompson, 2002). Co-stimulation can promote both early antigen-priming T cell activation and late T cell differentiation to effector or memory cells (Michael, 2003). At the same time, negative co-stimulatory signals may prevent unnecessary activation of T cells and hence autoimmune responses (Rothstein and Sayegh, 2003; Samia and Mohamed, 2004).

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abbas, A.K., Lichtman, A.H., and Pober, J.S. (1997). Cellular and Molecular Immunology. W.B. Saunders, Philadelphia, Pennsylvania.Google Scholar
  2. Adi, S., Wu, N.-Y., and Rosenthal, S.M. (2001). Growth factor-stimulated phosphorylation of Akt and p70S6K is differentially inhibited by LY294002 and wortmannin. Endocrinology, 142, 498–501.PubMedCrossRefGoogle Scholar
  3. Appleman, L.J., van Puijenbroek, A.A. F.L., Shu, K.M., Nadler, L.M., and Boussiotis, V.A. (2002). CD28 costimulation mediates down-regulation of p27kip1 and cell cycle progression by activating of the PI3K/PKB signaling pathway in primary human T cells. J. Immunol., 168, 2729–2736.PubMedGoogle Scholar
  4. Arch, R.H., and Thompson, C.B. (1998). 4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor κ B. Mol. Cell. Biol., 18, 558–565.PubMedGoogle Scholar
  5. Beginat, J., Sallusto, F., and Lanzavecchia, A. (2003). Cytokine-driven proliferation and differentiation of human naïve, central memory and effector memory CD4+ T cells. Pathologie Biologie., 51, 64–66.CrossRefGoogle Scholar
  6. Bertram, E.M., Lau, P., and Watts, T.W. (2002). Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection. J. Immunol., 168, 3777–3785.PubMedGoogle Scholar
  7. Botz, J., Zerfass-Thome, K., Spitzovsky, D., Delius, H., Vogt, B., Eilers, M., Hatzigeorgiou, A., and Jansen-Durr, P. (1996). Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter. Mol. Cell. Biol., 16, 3401–3409.PubMedGoogle Scholar
  8. Brennan, P., Babbage, J.W., Burgering, B.M.T., Groner, B., Reif, K., and Cantrell, D.A. (1997). Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity, 7, 679–689.PubMedCrossRefGoogle Scholar
  9. Brown, T.J., Emswiler, J., Raecho, H., Larsen, C.P., Pearson, T.C., Ledbetter, J.A., Aruffo, A., and Mittler. R.S. (1997). 4-1BB costimulatory signals preferentially induce CD8 T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med., 186, 47–55.PubMedCrossRefGoogle Scholar
  10. Burr, J.S., Savage, N.D., Messah, G.E., Kimzey, S.L., Shaw, A.S., Arch, R.H., and Green, J.M. (2001). Cutting edge: Distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL J. Immunol., 166, 5331–5335.PubMedGoogle Scholar
  11. Cannons, J.L., Choi, Y., and Watts, T.H. (2000). Role of TNF receptor-associated factor 2 and p38 mitogen-activated protein kinase activation during 4-1BB-dependent immune response. J. Immunol., 165, 6193–6204.PubMedGoogle Scholar
  12. Carreno, B.M., and Collins, M. (2002). The B7 family of ligands and its receptors: New pathways for costimulation and inhibition of immune responses. Annu. Rev. Immunol., 20, 29–53.PubMedCrossRefGoogle Scholar
  13. Chalupny, N.J., Peach, R., Hollenbaugh, D., Ledbetter, J.A., Farr, A.G., and Aaruffo, A. (1992). T-cell activation molecule 4-1BB binds to extracellular matrix proteins. Proc. Natl. Acad. Sci. USA., 89, 10360–10364.PubMedCrossRefGoogle Scholar
  14. Chambers, C.A., and Allison, J.P. (1999). Costimulatory regulation of T cell function. Curr. Opin. Cell. Biol., 11, 203–210.PubMedCrossRefGoogle Scholar
  15. Chan, F.K.-M., Siegel R.M., and Lenardo, M.J. (2000). Signaling by the TNF receptor superfamily and T cell homeostasis. Immunity, 13, 419–422.PubMedCrossRefGoogle Scholar
  16. Choi, B.K., Bae, J.S., Choi, E.M., Kang, W.J., Sakaguchi, S., Vinay, D.S., and Kwon, B.S. (2004). 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cell. J. Leukoc Biol., 75, 785–791.PubMedCrossRefGoogle Scholar
  17. Futagawa, T., Akiba, H., Kodama, T., Takeda, K., Hosoda, Y., and Yagita, H. (2002). Expression and function of 4-1BB and 4-1BB ligand on murine dendrine dendritic cells. Int. Immunol., 14, 275–286.PubMedCrossRefGoogle Scholar
  18. Gingras, A.-C., Raught, B., and Sonenberg, N. (2001). Regulation of translation initiation by FRAP/mTOR. Genes Dev., 15, 807–826.PubMedCrossRefGoogle Scholar
  19. Gravestein, L.A., Amsen, D., Boes, M., Calvo, C.R., Kruisbeek, A.M., and Borst, J. (1998). The TNF receptor family member CD27 signals to Jun N-terminal kinase via Traf-2. Eur. J. Immunol., 28, 2208–2216.PubMedCrossRefGoogle Scholar
  20. Gravestein, L.A., and Borst, J. (1998). Tumor necrosis factor receptor family members in the immune system. Semin. Immunol., 10, 423–434.PubMedCrossRefGoogle Scholar
  21. Grillot, D.A., Merino, R., and Nunez, G. (1995). Bcl-XL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice. J. Exp. Med., 182, 1973–1983.PubMedCrossRefGoogle Scholar
  22. Jang, I.K., Lee, Z.H., Kim, Y.-J., and Kwon. B.S. (1998). Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-κ B. Biophys. Biochem. Res. Commun., 242, 613–621.CrossRefGoogle Scholar
  23. Jones, R., Parsons, G.M., Bonnard, M., Chan, V.S.F., Yeh, W.-C., Woodgett, J.R., and Ohashi, P.S. (2000). Protein kinase B regulates T lymphocyte survival, nuclear factor κ B activation, and Bcl-XL levels in vivo. J. Exp. Med. 191, 1721–1734.Google Scholar
  24. June, C.H., Ledbetter, J.A., Linsley, P.S., and Thompson, C.B. (1990). Role of the CD28 receptor in T-cell activation. Immunol. Today, 11, 211–216.PubMedCrossRefGoogle Scholar
  25. Kanegane, H., and Tosato, G. (1996). Activation of naïve and memory T cells by interleukin-15. Blood, 88, 230–235.PubMedGoogle Scholar
  26. Kenneth, A. T., and Thompson, C. B. (2002). Activation and Inhibition of lymphocytes by costimulation. J. Clin. Invest., 109, 295–299.CrossRefGoogle Scholar
  27. Khoshnan, A., Tindell, C., Laux, I., Bae, D., Bennett, B., and Nel, A.E. (2000). The NF-κ B cascade is important in Bcl-XL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes. J. Immunol., 165, 1743–1749.PubMedGoogle Scholar
  28. Kim, Y.J., Brutkiewicz, R.R., and Broxmeyer, H.E. (2002). Role of 4-1BB (CD137) in the functional activation of cord blood. Blood, 100, 3253 and 3260.PubMedCrossRefGoogle Scholar
  29. Kim, Y.Z., Mantel, P.L., June, C.H., Kim, S.H., and Kwon, B.S. (1999). 4-1BB costimulation promotes human T cell adhesion to fibronectin. Cell. Immunol., 192, 13–21.PubMedCrossRefGoogle Scholar
  30. Kuo, C.J., Chung, J., Fiorentino, D.F., Flanagan, W.M., Blenis, J., and Crabtree, G.R. (1992). Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature, 358, 70–73.PubMedCrossRefGoogle Scholar
  31. Kwon, B., Lee, H.W., and Kwon, B.S. (2002). New insights into the role of 4-1BB in immune response: Beyond CD8+ T cells. Trend Immunol., 23, 378–380.CrossRefGoogle Scholar
  32. Kwon, B., Moon, C.H., Seo, S.K., and Kwon, B.S. (2000). 4-1BB: Still in the midst of darkness. Mol. Cells, 30, 119–126.CrossRefGoogle Scholar
  33. Kwon, B.S., and Weissman, S.M. (1989). cDNA sequences of two inducible T-cell genes. Proc. Natl Acad. Sci. USA., 86, 1963–1967.PubMedCrossRefGoogle Scholar
  34. Lantz, O., Grandhean, I., Matzinger, P., and Di Santo, J.P. (2000). Gamma chain required for naïve CD4+ T cell survival but not for antigen proliferation. Nat. Immunol., 1, 54–58.PubMedCrossRefGoogle Scholar
  35. Lee, H.H., Dadgostar, H., Cheng, Q., Shu, J., and Cheng, G. (1999). NF-κ B-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proc. Natl. Acad. Sci. USA., 96, 9136–9141.PubMedCrossRefGoogle Scholar
  36. Lee, H.W., Nam, K.O., Park. S.J., and Kwon, B.S. (2003a). 4-1BB Enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D2 and E and cyclin-dependent kinase inhibitor p27kip1. Eur. J. Immunol., 33, 2133–2141.CrossRefGoogle Scholar
  37. Lee, H.W., Nam, K.O., Seo, S.K., Kim, Y.H., Kang, H., and Kwon, B.S. (2003b). 4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes. Cellular Immunol., 223, 143–150.CrossRefGoogle Scholar
  38. Lee, H.W., Park, S.J., Choi, B.K., Kim, H.H., Nam, K.O., and Kwon, B.S. (2002). 4-1BB promotes the survival of CD8+T lymphocytes by increasing expression of Bcl-XL and Bfl-1. J. Immunol., 169, 4882–4888.PubMedGoogle Scholar
  39. Lenschow, D.J., Walunas, T.L., and Bluestone, J.A. (1996). CD28/B7 system of T cell costimulation. Annu. Rev. Immunol., 14, 233–258.PubMedCrossRefGoogle Scholar
  40. Leone, G., DeGregori, J., Sears, R., Jakoi, L., and Nevins, H. (1997). Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature, 387, 422–426.PubMedCrossRefGoogle Scholar
  41. Lodolce, J.P., Boone, D.L., Chai, S., Swain, R.E., Dassopoulos, T., Trettin, S., and Ma, A. (1998). IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity, 9, 669–676.PubMedCrossRefGoogle Scholar
  42. Marwali, M.R., Rey-Ladino, J., Dreolini, L., Shaw, D., and Takei, F. (2003). Membrane cholesterol regulates LFA-1 function and lipid raft heterogeneity. Blood, 102, 215–222.PubMedCrossRefGoogle Scholar
  43. Matakeyama, M., Brill, J.A., Fink, G.R., and Weinberg, R.A. (1994). Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev., 8, 1759–1771.CrossRefGoogle Scholar
  44. Melero, I., Shuford, W.W., Newby, S.A., Aruffo, A., Ledbetter, J.A., Hellstrom, K.E., Mittler, R.S., and Chen, L. (1997). Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med., 3, 682–685.PubMedCrossRefGoogle Scholar
  45. Michael, C. (2003). Costimulation of T cells by OX40, 4-1BB, and CD27. Cytokine Growth Factor Rev., 14, 265–273.CrossRefGoogle Scholar
  46. Montagnoli, A., Fiore, F., Eytan, E., Carrano, A.C., Draetta, G.F., Hershko, A., and Pagano, M., (1999). Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev., 13, 1181–1189.PubMedGoogle Scholar
  47. Moon, J.J., and Nelson, B.H. (2001). Phosphatidylinositol 3-kinase potentiates, but does not trigger, T cell proliferation mediated by the IL-2 receptor. J. Immunol., 167, 2714–2723.PubMedGoogle Scholar
  48. Mueller, D.L. (2000). T cell: A proliferation of costimulatory molecules. Curr. Biol., 10, R227–R230.PubMedCrossRefGoogle Scholar
  49. Mueller, D.L., Jenkins, M.K., and Schwarz, R.H. (1989). Clonal expansion versus functional clonal inactivation: a costimulatory signaling pathway determines the outcome of T cell antigen receptor occupancy. Annu. Rev. Immunol., 7, 445–480.PubMedGoogle Scholar
  50. Nakajima, H., Shores, E.W., Noguchi, M., and Leonard, W.J. (1997). The common cytokine receptor gamma chain plays an essential role in regulating lymphoid homeostasis. J. Exp. Med., 185, 189–195.PubMedCrossRefGoogle Scholar
  51. Nam, K.O., Kang, H.S., Shin, M., Cho, K.H., Kwon, B., Kwon, B.S., Kim, S.J., and Lee, H.W. (2005). Cross-linking of 4-1BB activates TCR-signaling pathways in CD8+ T lymphocytes. J. Immunol., 174, 1898–1905.PubMedGoogle Scholar
  52. Okkenhaung, K., Wu, L., Garza, K.M., La Rose, J., Khoo, W., Odermatt, B., and Mak T.K. (2001). A point mutation in CD28 distinguishes proliferative signals from survival signals. Nat. Immunol., 2, 325–332.CrossRefGoogle Scholar
  53. Ozes, O.N., Mayo, L.D., Gustin, J.A., Pfeffer, S.R., Pfeffer, L.M., and Donner, D.B. (1999). NF-κ B activation by tumour necrosis factor requires the Akt serine-theonine kinase. Nature, 401, 82–85.PubMedCrossRefGoogle Scholar
  54. Pan, P.Y., Gu, P., Li, Q., Xu, D., Weber, K., and Chen, S.H. (2004). Regulation of Dendritic Cell Function by NK Cell: Mechanisms Underlying the Synergism in the Combination Therapy of IL-12 and 4-1BB Activation. J. Immunol., 172, 4779–4789.PubMedGoogle Scholar
  55. Poltak, K., Kato, J.-Y., Solomon, M.J., Sherr, C.J., Massague, J., Roberts, J.M., and Koff, A. (1994). p27Kip1, a cyclin-cdk inhibitor, links transforming growth factor-b and contact inhibition to cell cycle arrest. Genes Dev., 8, 9–22.CrossRefGoogle Scholar
  56. Resnitzky, D., and Reed, S.I. (1995). Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Mol. Cell. Biol., 15, 3463–3469.PubMedGoogle Scholar
  57. Rothstein, D.M., and Sayegh, M.H. (2003). T-cell costimulatory pathways in allograft rejection and tolerance. Immunol. Rev., 196, 85–108.PubMedCrossRefGoogle Scholar
  58. Salazar, E.P, and Rozengurt, E. (1999). Bombesin and platelet-derived growth factor induce association of endogenous focal adhesion kinase with Src in intact Swiss 3T3 cells. J. Biol. Chem., 274, 28371–28378.PubMedCrossRefGoogle Scholar
  59. Samia, J.K., and Mohamed, H.S. (2004). The Roles of the new negative T cell costimulatory pathways in regulating autoimmunity. Immunity, 20, 529–538.CrossRefGoogle Scholar
  60. Saoulli, K., Lee, S.Y., Cannons, J.L., Yeh W.C., Santana, A., Goldstein, M.D., Bangia, N., DeBenedette, M.A., Mak, T.W., Choi, Y., and Watts, T. H. (1998). CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J. Exp. Med., 187, 1849–1862.PubMedCrossRefGoogle Scholar
  61. Schluns, K.S., Kieper, W.C., Jameson, S.C., and Lefrancois, L. (2000). Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol., 1, 426–432.PubMedCrossRefGoogle Scholar
  62. Schwarz, H., Tuckwell, J., and Lotz, M. (1993). A receptor-induced by lymphocyte activation (ILA): A new member of the human nerve growth factor/tumor necrosis factor receptor family. Gene, 134, 295–298.PubMedCrossRefGoogle Scholar
  63. Sherr, C.J., and Roberts, J.M. (1999). CDK inhibitors: Positive and negative regulators of G1-phase progression. Genes Dev., 13, 1501–1512.PubMedGoogle Scholar
  64. Seo, S.K., Choi, J.H., Kim, Y.H., Young, H., Kang, W.J., Suh, J.H., Choi, B. K., Vinay, B.S., and Kwon, B.S. (2004). 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat. Med., 10, 1088–1094.PubMedCrossRefGoogle Scholar
  65. Shuford, W.W., Klussman, K., Tritchler, D.D., Loo, D.K., Chalupny, J., Siadak, A.W., Brown, T.J., Emswiler, J., Raecho, H., Larsen, C.P., Pearson, T.C., Ledbetter, J.A., Aruffo, A., and Mittler, R.S. (1997). 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med., 186, 46–55.CrossRefGoogle Scholar
  66. Tan, J.T., Ha, J., Cho, H.R., Tucker-Burden C., Hendrix, R.C., Mittler, R.S., Pearson, T.C., and Larsen, C.P. (2000). Analysis of expression and function of the costimulatory molecule 4-1BB in alloimmune responses. Transplantation, 70, 175–183.PubMedGoogle Scholar
  67. Toyoshima, H., and Hunter, T. (1994). p27, a novel inhibitor of G1 cyclin/Cdk protein kinase activity, is related to p21. Cell, 78, 67–74.PubMedCrossRefGoogle Scholar
  68. Tsvetkov, L.M., Yeh, K.H., Lee, S.J., Sun, H., and Zhang, H. (1999). p27 (Kip1) ubiquitination and degradation is regulated by the SCF (Skp2) complex through phosphorylated Thr187 in p27. Curr. Biol., 9, 661–664.PubMedCrossRefGoogle Scholar
  69. Unutmaz, D., Baldoni, F., and Abrignani, S. (1995). Human naïve T Cells activated by cytokines differentiate into a split phenotype with functional features intermediate between naïve and memory T cells. Int. Immunol., 7, 1417–1424.PubMedCrossRefGoogle Scholar
  70. Unutmaz, D., Pileri, P., and Abrignani, S. (1994). Antigen-independent activation of naïve and memory resting T cell by a cytokine combination. J. Exp. Med., 180, 1159–1164.PubMedCrossRefGoogle Scholar
  71. Van Parijs, L., and Abbas, A.K. (1998). Homeostasis and self-tolerance in the immune system: Turning lymphocytes off. Science, 280, 243–248.PubMedCrossRefGoogle Scholar
  72. Vidalain, P.O., Azocar, O., Servet-Delprat, C., Rabourdin-Combe, C., Gerlier, D., and Manie, S. (2000). CD40 signaling in human dendritic cells is initiated within membrane rafts. EMBO J., 19, 3304–3313.PubMedCrossRefGoogle Scholar
  73. Vinay, D.S., and Kwon, B.S. (1998). Role of 4-1BB in immune response. Semin. Immunol., 10, 481–489.PubMedCrossRefGoogle Scholar
  74. Vlahos, C.J., Matter, W.F., Hui, K.Y., and Brown, R.F., (1994). A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem., 269, 5241–5248.PubMedGoogle Scholar
  75. Watts, T.H., and DeBenedette, M.A. (1999). T cell co-stimulatory molecules other than CD28. Curr. Opin. Immunol., 11, 286–293.PubMedCrossRefGoogle Scholar
  76. Weinberg, A.D., Vella, A.T., and Croft, M. (1998). Ox-40: Life beyond the effector T cell stage. Semin. Immunol., 10, 471–480.PubMedCrossRefGoogle Scholar
  77. Wilcox, R.A., Chapoval, A.I., Gorski, K.S., Otsuji, M., Shin, T., Flies, D.B., Tamada, K., Mittler, R.S., Tsuchiya, H., Pardoll, D.M., and Chen, L. (2002). Cutting edge: Expression of functional CD137 receptor by dendritic cells. J Immunol., 168, 4262–4267.PubMedGoogle Scholar
  78. Ye, H., Park, Y.C., Kreishman, M., Kieff, E., and Wu, H. (1999). The structure basis for the recognition of diverse receptor sequence by TRAF2. Mol. Cell, 4, 321–330.PubMedCrossRefGoogle Scholar
  79. Zhang, X., Sun, S., Hwang, I., Tough, D.F., and Sprent, J. (1998). Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity, 8, 591–599.PubMedCrossRefGoogle Scholar
  80. Zheng, G., Wang, B., and Chen, A. (2004). The 4-1BB Costimulation Augments the Proliferation of CD4+CD25+ Regulatory T Cell. J. Immunol., 173, 2428–2434.PubMedGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • Hyeon-Woo Lee
    • 1
  • Byoung S. Kwon
    • 2
    • 3
  1. 1.Department of Pharmacology, School of DentistryKyung Hee UniversitySeoulKorea
  2. 2.Immunomodulation Research CenterUniversity of UlsanUlsanKorea
  3. 3.LSU Eye CenterNew Orleans

Personalised recommendations