Advertisement

Molecules and Cells

, Volume 36, Issue 5, pp 455–464 | Cite as

Human cytomegalovirus (HCMV) US2 protein interacts with human CD1d (hCD1d) and down-regulates invariant NKT (iNKT) cell activity

  • Jihye Han
  • Seung Bae Rho
  • Jae Yeon Lee
  • Joonbeom Bae
  • Se Ho Park
  • Suk Jun Lee
  • Sang Yeol Lee
  • Curie Ahn
  • Jae Young Kim
  • Taehoon ChunEmail author
Research Article

Abstract

To avoid host immune surveillance, human cytomegalovirus (HCMV) encoded endoplasmic reticulum (ER)-membrane glycoprotein US2, which interferes with antigen presenting mechanism of Major histocompatibility complex (MHC) class Ia and class II molecules. However, not many attempts have been made to study the effect of HCMV US2 on the expression of MHC class Ib molecules. In this study, we examined the effect of HCMV US2 on the expression and function of human CD1d (hCD1d), which presents glycolipid antigens to invariant NKT (iNKT) cells. Our results clearly showed that the physiological interaction between ER lumenal domain of HCMV US2 and α3 domain of hCD1d was observed within ER. Compared with mature form of hCD1d, immature form of hCD1d is more susceptible to ubiquitin-dependent proteasomal degradation mediated by HCMV US2. Moreover, the ectopic expression of HCMV US2 leads to the down-modulation of iNKT cell activity without significant change of hCD1d expression. These results will advance our understanding of the function of HCMV US2 in immune evasive mechanisms against anti-viral immunity of iNKT cells.

Keywords

antigen presentation HCMV US2 protein human CD1d human cytomegalovirus invariant NKT cell 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Balk, S.P., Burke, S., Polischuk, J.E., Frantz, M.E., Yang, L., Porcelli, S., Colgan, S.P., and Blumberg, R.S. (1994). β2-microglobulin-independent MHC class Ib molecule expressed by human intestinal epithelium. Science 265, 259–262.PubMedCrossRefGoogle Scholar
  2. Bendelac, A., Savage, P.B., and Teyton, L. (2007). The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336.PubMedCrossRefGoogle Scholar
  3. Chackerian, A., Alt, J., Perera, V., and Behar, S.M. (2002). Activation of NKT cells protects Mice from tuberculosis. Infect. Immun. 70, 6302–6309.PubMedCrossRefGoogle Scholar
  4. Chevalier, M.S., Daniels, G.M., and Johnson, D.C. (2002). Binding of human cytomegalovirus US2 to major histocompatibility complex class I and II proteins is not sufficient for their degradation. J. Virol. 76, 8265–8275.PubMedCrossRefGoogle Scholar
  5. Cho, S., and Jun, Y. (2011). Human CD1d molecules are resistant to human cytomegalovirus US2- and US11-mediated degradation. Biochem. Biophys. Res. Commun. 413, 616–622.PubMedCrossRefGoogle Scholar
  6. Cho, S., and Hwang, E.S. (2012). Status of mTOR activity may phenotypically differentiate senescence and quiescence. Mol. Cells 33, 597–604.PubMedCrossRefGoogle Scholar
  7. Cohen, N.R., Garg, S., and Brenner, M.B. (2009). Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94.PubMedGoogle Scholar
  8. De Santo, C., Salio, M., Masri, S.H., Lee, L.Y., Dong, T., Speak, A.O., Porubsky, S., Booth, S., Veerapen, N., Besra, G.S., et al. (2008). Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J. Clin. Invest. 118, 4036–4048.PubMedCrossRefGoogle Scholar
  9. Dougan, S.K., Salas, A., Rava, P., Agyemang, A., Kaser, A., Morrison, J., Khurana, A., Kronenberg, M., Johnson, C., Exley, M., et al. (2005). Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells. J. Exp. Med. 202, 529–539.PubMedCrossRefGoogle Scholar
  10. Furman, M.H., Ploegh, H.L., and Schust, D.J. (2000). Can viruses help us to understand and classify the MHC class I molecules at the maternal-fetal interface? Hum. Immunol. 61, 1169–1176.PubMedCrossRefGoogle Scholar
  11. Gewurz, B.E., Gaudet, R., Tortorella, D., Wang, E.W., Ploegh, H.L., and Wiley, D.C. (2001). Antigen presentation subverted: structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2. Proc. Natl. Acad. Sci. USA 98, 6794–6799.PubMedCrossRefGoogle Scholar
  12. Gewurz, B.E., Ploegh, H.L., and Tortorella, D. (2002). US2, a human cytomegalovirus-encoded type I membrane protein, contrains a non-cleavable amino-terminal signal peptide. J. Biol. Chem. 277, 11306–11313.PubMedCrossRefGoogle Scholar
  13. Gonzalez-Aseguinolaza, G., de Oliveira, C., Tomaska, M., Hong, S., Bruna-Romero, O., Nakayama, T., Taniguchi, M., Bendelac, A., Van Kaer, L., Koezuka, Y., et al. (2000). alpha-galactosylceramide-activated Valpha 14 natural killer T cells mediate protection against murine malaria. Proc. Natl. Acad. Sci. USA 97, 8461–8466.PubMedCrossRefGoogle Scholar
  14. Grubor-Bauk, B., Simmons, A., Mayrhofer, G., and Speck, P.G. (2003). Impared clearance of herpes simplex virus type 1 from mice lacking CD1d or NKT cells expressing the semivariant Vα14-Jα281 TCR. J. Immunol. 170, 1430–1434.PubMedGoogle Scholar
  15. Hansen, T.H., Huang, S., Arnold, P.L., and Fermont, D.H. (2007). Patterns of nonclassical MHC antigen presentation. Nat. Immunol. 8, 563–568.PubMedCrossRefGoogle Scholar
  16. Ilyinskii, P.O., Wang, R., Balk, S.P., and Exley, M.A. (2006). CD1d mediates T-cell-Dependent resistance to secondary infection with encephalomyocarditis virus (EMCV) in vitro and immune response to EMCV infection in vivo. J. Virol. 80, 7146–7158.PubMedCrossRefGoogle Scholar
  17. Jayawardena-Wolf, J., Benlagha, K., Chiu, Y.H., Mehr, R., and Bendelac, A. (2001). CD1d endosomal trafficking is independently regulated by an intrinsic CD1d-encoded tyrosine motif and by the invariant chain. Immunity 15, 897–908.PubMedCrossRefGoogle Scholar
  18. Johnson, T.R., Hong, S., Van Kaer, L., Koezuka, Y., and Graham, B.S. (2002). NKT cells contribute to expansion of CD8+ T cells and amplification of antiviral immune responses to respiratory syncytial virus. J. Virol. 76, 4294–4303.PubMedCrossRefGoogle Scholar
  19. Kakimi, K., Guidotti, L.G., Koezuka, Y., and Chisari, F.V. (2000). Natural killer T cell activation inhibits hepatitis B virus replication in vivo. J. Exp. Med. 192, 921–930.PubMedCrossRefGoogle Scholar
  20. Kang, S.J., and Cresswell, P. (2002). Calnexin, calreticulin, and ERp57 cooperate in disulfide bond formation in human CD1d heavy chain. J. Biol. Chem. 277, 44838–44844.PubMedCrossRefGoogle Scholar
  21. Kawana, K., Quayle, A.J., Ficarra, M., Ibana, J.A., Shen, L., Kawana, Y., Yang, H., Marrero, L., Yavagal, S., Greene, S.J., et al. (2007). CD1d degradation in Chlamydia trachomatis-infected epithelial cells is the result of both cellular and chlamydial proteasomal activity. J. Biol. Chem. 282, 7368–7375.PubMedCrossRefGoogle Scholar
  22. Kawano, T., Cui, J., Koezuka, Y., Toura, I., Kaneko, Y., Motoki, K., Ueno, H., Nakagawa, R., Sato, H., Kondo, E., et al. (1997). CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science 278, 1626–1629.PubMedCrossRefGoogle Scholar
  23. Kawano, T., Cui, J., Koezuka, Y., Toura, I., Kaneko, Y., Sato, H., Kondo, E., Harada, M., Koseki, H., Nakayama, T., et al. (1998). Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Valpha14 NKT cells. Proc. Natl. Acad. Sci. USA 95, 5690–5693.PubMedCrossRefGoogle Scholar
  24. Kim, H.S., Garcia, J., Exley, M., Johnson, K.W., Balk, S.P., and Blumberg, R.S. (1999). Biochemical characterization of CD1d expression in the absence of beta2-microglobulin. J. Biol. Chem. 274, 9289–9295.PubMedCrossRefGoogle Scholar
  25. Kim, E.M., Lee, H.H., Kim, S.H., Son, Y.O., Lee, S.J., Han, J., Bae, J., Kim, S.J., Park, C.G., Park, Y., et al. (2011). The mouse small ubiquitin-like modifier-2 (SUMO-2) inhibits interleukin-12 (IL-12) production in mature dendritic cells by blocking the translocation of the p65 subunit of NFκB into the nucleus. Mol. Immunol. 48, 2189–2197.PubMedCrossRefGoogle Scholar
  26. Körner, H., and Burgert, H.G. (1994). Down-regulation of HLA antigens by the adenovirus type 2 E3/19K protein in a T-lymphoma cell line. J. Virol. 68, 1442–1448.PubMedGoogle Scholar
  27. Lee, J.H., Rho, S.B., Park, S.Y., and Chun, T. (2008). Interaction between fortilin and transforming growth factor-beta stimulated clone-22 (TSC-22) prevents apoptosis via the destabilization of TSC-22. FEBS Lett. 582, 1210–1218.PubMedCrossRefGoogle Scholar
  28. Lin, Y., Roberts, T.J., Spence, P.M., and Brutkiewicz, R.R. (2005). Reduction in CD1d expression on dendritic cells and macrophages by an acute virus infection. J. Leukoc. Biol. 77, 151–158.PubMedCrossRefGoogle Scholar
  29. Moody, D.B., Zajonc, D.M., and Wilson, I.A. (2005). Anatomy of CD1-lipid antigen complexes. Nat. Rev. Immunol. 5, 387–399.PubMedCrossRefGoogle Scholar
  30. Park, S.H., Roark, J.H., and Bendelac, A. (1998). Tissue-specific recognition of mouse CD1 molecules. J. Immunol. 160, 3128–3134.PubMedGoogle Scholar
  31. Pinto, A.K., and Hill, A.B. (2005). Viral interference with antigen presentation to CD8+ T cells, lessons from cytomegalovirus. Viral Immunol. 18, 434–444.PubMedCrossRefGoogle Scholar
  32. Ploegh, H.L. (1998). Viral strategies of immune evasion. Science 280, 249–253.CrossRefGoogle Scholar
  33. Raftery, M.J., Hitzler, M., Winau, F., Giese, T., Plachter, B., Kaufmann, S.H., and Schonrich, G. (2008). Inhibition of CD1 antigen presentation by human cytomegalovirus. J. Virol. 82, 4308–4319.PubMedCrossRefGoogle Scholar
  34. Rodgers, J.R., and Cook, R.G. (2005). MHC class Ib molecules bridge innate and acquired immunity. Nat. Rev. Immunol. 5, 459–471.PubMedCrossRefGoogle Scholar
  35. Sanchez, D.J., Gumperz, J.E., and Ganem, D. (2005). Regulation of CD1d expression and function by a herpesvirus infection. J. Clin. Invest. 115, 1369–1378.PubMedGoogle Scholar
  36. Schust, D.J., Tortorella, D., Seebach, J., Phan, C., and Ploegh, H.L. (1998). Trophoblast class I major histocompatibility complex (MHC) products are resistant to rapid degradation imposed by the human cytomegalovirus (HCMV) gene products US2 and US11. J. Exp. Med. 188, 497–503.PubMedCrossRefGoogle Scholar
  37. Seriger, B., Ritz, U., and Ferrone, S. (2006). Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation. Int. J. Cancer 118, 129–138.CrossRefGoogle Scholar
  38. Storkus, W.J., Howell, D.N., Salter, R.D., Dawson, J.R., and Cresswell, P. (1987). NK susceptibility varies inversely with target cell class I HLA antigen expression. J. Immunol. 138, 1657–1659.PubMedGoogle Scholar
  39. Tomazin, R., Boname, J., Hegde, N.R., Lewinsohn, D.M., Altschuler, Y., Jones, T.R., Cresswell, P., Nelson, J.A., Riddell, S.R., and Johnson, D.C. (1999). Cytomegalovirus US2 destroys two components of the MHC class II pathways, preventing recognition by CD4+ T cells. Nat. Med. 5, 1039–1043.PubMedCrossRefGoogle Scholar
  40. van Dommelen, S.L., Tabarias, H.A., Smyth, M.J., and Degli-Esposti, M.A. (2003). Activation of NKT cells during murine cytomegalovirus infection enhances the antiviral response mediated by NK cells. J. Virol. 77, 1877–1894.PubMedCrossRefGoogle Scholar
  41. Wang, B., Geng, Y.B., and Wang, C.R. (2001). CD1-restricted NKT cells protect nonobese Diabetic mice from developing diabetes. J. Exp. Med. 194, 313–320.PubMedCrossRefGoogle Scholar
  42. Wiertz, E.J., Tortorella, D., Bogyo, M., Yu, J., Mothes, W., Jones, T.R., Rapoport, T.A., and Ploegh, H.L. (1996). Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438.PubMedCrossRefGoogle Scholar
  43. Yang, J.Q., Chun, T., Liu, H., Hong, S., Bui, H., Van Kaer, L., Wang, C.R., and Singh, R.R. (2004). CD1d deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice. Eur. J. Immunol. 34, 1723–1732.PubMedCrossRefGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2013

Authors and Affiliations

  • Jihye Han
    • 1
  • Seung Bae Rho
    • 2
  • Jae Yeon Lee
    • 1
  • Joonbeom Bae
    • 1
  • Se Ho Park
    • 1
  • Suk Jun Lee
    • 3
  • Sang Yeol Lee
    • 4
  • Curie Ahn
    • 5
  • Jae Young Kim
    • 4
  • Taehoon Chun
    • 1
    Email author
  1. 1.School of Life Sciences and BiotechnologyKorea UniversitySeoulKorea
  2. 2.Research Institute and HospitalNational Cancer CenterGoyangKorea
  3. 3.Department of Biomedical Laboratory ScienceGimcheon UniversityGimcheonKorea
  4. 4.Department of Life Sciences, College of BionanoGachon UniversitySeongnamKorea
  5. 5.Department of Internal Medicine, College of MedicineSeoul National UniversitySeoulKorea

Personalised recommendations