1887

Journal of General Virology header logo

Volume 89, Issue 10

Human cytomegalovirus infection interferes with major histocompatibility complex type II maturation and endocytic proteases in dendritic cells at multiple levels Free

Abstract

Human cytomegalovirus (HCMV) infection suppresses cellular immunity and results in viral persistence. Dendritic cells (DCs) are susceptible to HCMV, and the development and immune function of HCMV-infected DCs are impaired . HCMV-derived proteins interfere with different aspects of major histocompatibility complex type II (MHC II) maturation and function in genetically engineered cellular models. This study directly analysed the effect of HCMV on the MHC II-associated antigen processing and presentation machinery in HCMV-infected human DCs . HCMV-infected DCs failed to mature newly synthesized MHC II to the final stage of SDS-stable MHC II dimer/peptide complexes, in contrast to mock-infected controls. MHC II biosynthesis was delayed and reduced, whilst MHC II stability remained unchanged. MHC II surface expression was decreased in the late phase of HCMV infection. In addition, infected DCs decreased the transcription rate of the MHC II-associated proteases cathepsins S, Z, B, H and L and asparagine-specific endopeptidase (AEP). This translated into reduced protein expression of cathepsins H and S, as well as AEP, and less-efficient proteolytic degradation of a peptide substrate by endocytic proteases from HCMV-infected DCs . Thus, HCMV infection interferes with MHC II biosynthesis and maturation, as well as with the expression and function of endocytic proteases in infected DCs.

  • Received:
  • Accepted:
  • Published Online:
SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.2008/001610-0
2008-10-01
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/10/2427.html?itemId=/content/journal/jgv/10.1099/vir.0.2008/001610-0&mimeType=html&fmt=ahah

References

  1. Beck H., Schwarz G., Schröter C. J., Deeg M., Baier D., Stevanovic S., Weber E., Driessen C., Kalbacher H. 2001; Cathepsin S and an asparagine-specific endoprotease dominate the proteolytic processing of human myelin basic protein in vitro. Eur J Immunol 31:3726–3736 [CrossRef]
     [Google Scholar]
  2. Beck K., Meyer-König U., Weidmann M., Nern C., Hufert F. T. 2003; Human cytomegalovirus impairs dendritic cell function: a novel mechanism of human cytomegalovirus immune escape. Eur J Immunol 33:1528–1538 [CrossRef]
     [Google Scholar]
  3. Burster T., Beck A., Tolosa E., Schnorrer P., Weissert R., Reich M., Kraus M., Kalbacher H., Häring H. U. other authors 2005; Differential processing of autoantigens in lysosomes from human monocyte-derived and peripheral blood dendritic cells. J Immunol 175:5940–5949 [CrossRef]
     [Google Scholar]
  4. Dengjel J., Schoor O., Fischer R., Reich M., Kraus M., Müller M., Kreymborg K., Altenberend F., Brandenburg J. other authors 2005; Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc Natl Acad Sci U S A 102:7922–7927 [CrossRef]
     [Google Scholar]
  5. Dolan A., Cunningham C., Hector R. D., Hassan-Walker A. F., Lee L., Addison C., Dargan D. J., McGeoch D. J., Gatherer D. other authors 2004; Genetic content of wild-type human cytomegalovirus. J Gen Virol 85:1301–1312 [CrossRef]
     [Google Scholar]
  6. Driessen C., Bryant R. A., Lennon-Duménil A. M., Villadangos J. A., Bryant P. W., Shi G. P., Chapman H. A., Ploegh H. L. 1999; Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells. J Cell Biol 147:775–790 [CrossRef]
     [Google Scholar]
  7. George M. J., Snydman D. R., Werner B. G., Griffith J., Falagas M. E., Dougherty N. N., Rubin R. H. 1997; The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Am J Med 103:106–113 [CrossRef]
     [Google Scholar]
  8. Greiner A., Lautwein A., Overkleeft H. S., Weber E., Driessen C. 2003; Activity and subcellular distribution of cathepsins in primary human monocytes. J Leukoc Biol 73:235–242 [CrossRef]
     [Google Scholar]
  9. Grigoleit U., Riegler S., Einsele H., Laib Sampaio K., Jahn G., Hebart H., Brossart P., Frank F., Sinzger C. 2002; Human cytomegalovirus induces a direct inhibitory effect on antigen presentation by monocyte-derived immature dendritic cells. Br J Haematol 119:189–198 [CrossRef]
     [Google Scholar]
  10. Hegde N. R., Tomazin R. A., Wisner T. W., Dunn C., Boname J. M., Lewinsohn D. M., Johnson D. C. 2002; Inhibition of HLA-DR assembly, transport, and loading by human cytomegalovirus glycoprotein US3: a novel mechanism for evading major histocompatibility complex class II antigen presentation. J Virol 76:10929–10941 [CrossRef]
     [Google Scholar]
  11. Jahn G., Stenglein S., Riegler S., Einsele H., Sinzger C. 1999; Human cytomegalovirus infection of immature dendritic cells and macrophages. Intervirology 42:365–372 [CrossRef]
     [Google Scholar]
  12. Lee A. W., Hertel L., Louie R. K., Burster T., Lacaille V., Pashine A., Abate D. A., Mocarski E. S., Mellins E. D. 2006; Human cytomegalovirus alters localization of MHC class II and dendrite morphology in mature Langerhans cells. J Immunol 177:3960–3971 [CrossRef]
     [Google Scholar]
  13. Loenen W. A., Bruggeman C. A., Wiertz E. J. 2001; Immune evasion by human cytomegalovirus: lessons in immunology and cell biology. Semin Immunol 13:41–49 [CrossRef]
     [Google Scholar]
  14. Manoury B., Hewitt E. W., Morrice N., Dando P. M., Barrett A. J., Watts C. 1998; An asparaginyl endopeptidase processes a microbial antigen for class II MHC presentation. Nature 396:695–699 [CrossRef]
     [Google Scholar]
  15. Moutaftsi M., Mehl A. M., Borysiewicz L. K., Tabi Z. 2002; Human cytomegalovirus inhibits maturation and impairs function of monocyte-derived dendritic cells. Blood 99:2913–2921 [CrossRef]
     [Google Scholar]
  16. Nichols W. G., Corey L., Gooley T., Davis C., Boeckh M. 2002; High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis 185:273–282 [CrossRef]
     [Google Scholar]
  17. Odeberg J., Plachter B., Branden L., Söderberg-Nauclér C. 2003; Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR α -chain. Blood 101:4870–4877 [CrossRef]
     [Google Scholar]
  18. Pierre P., Mellman I. 1998; Developmental regulation of invariant chain proteolysis controls MHC class II trafficking in mouse dendritic cells. Cell 93:1135–1145 [CrossRef]
     [Google Scholar]
  19. Ploegh H. L. 1998; Viral strategies of immune evasion. Science 280:248–253 [CrossRef]
     [Google Scholar]
  20. Rehm A., Engelsberg A., Tortorella D., Körner I. J., Lehmann I., Ploegh H. L., Höpken U. E. 2002; Human cytomegalovirus gene products US2 and US11 differ in their ability to attack major histocompatibility class I heavy chains in dendritic cells. J Virol 76:5043–5050 [CrossRef]
     [Google Scholar]
  21. Reich M., van Swieten P. F., Sommandas V., Kraus M., Fischer R., Weber E., Kalbacher H., Overkleeft H. S., Driessen C. 2007; Endocytosis targets exogenous material selectively to cathepsin S in live human dendritic cells, while cell-penetrating peptides mediate nonselective transport to cysteine cathepsins. J Leukoc Biol 81:990–1001 [CrossRef]
     [Google Scholar]
  22. Riegler S., Hebart H., Einsele H., Brossart P., Jahn G., Sinzger C. 2000; Monocyte-derived dendritic cells are permissive to the complete replicative cycle of human cytomegalovirus. J Gen Virol 81:393–399
     [Google Scholar]
  23. Schrier R. D., Rice G. P., Oldstone M. B. 1986; Suppression of natural killer cell activity and T cell proliferation by fresh isolates of human cytomegalovirus. J Infect Dis 153:1084–1091 [CrossRef]
     [Google Scholar]
  24. Sénéchal B., Boruchov A. M., Reagan J. L., Hart D. N., Young J. W. 2004; Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83. Blood 103:4207–4215 [CrossRef]
     [Google Scholar]
  25. Simmons P., Kaushansky K., Torok-Storb B. 1990; Mechanisms of cytomegalovirus-mediated myelosuppression: perturbation of stromal cell function versus direct infection of myeloid cells. Proc Natl Acad Sci U S A 87:1386–1390 [CrossRef]
     [Google Scholar]
  26. Sinzger C., Schmidt K., Knapp J., Kahl M., Beck R., Waldman J., Hebart H., Einsele H., Jahn G. 1999; Modification of human cytomegalovirus tropism through propagation in vitro is associated with changes in the viral genome. J Gen Virol 80:2867–2877
     [Google Scholar]
  27. Sinzger C., Hahn G., Digel M., Katona R., Sampaio K. L., Messerle M., Hengel H., Koszinowski U., Brune W., Adler B. 2008; Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E. J Gen Virol 89:359–368 [CrossRef]
     [Google Scholar]
  28. Söderberg-Nauclér C., Nelson J. Y. 1999; Human cytomegalovirus latency and reactivation – a delicate balance between the virus and its host's immune system. Intervirology 42:314–321 [CrossRef]
     [Google Scholar]
  29. Söderberg-Nauclér C., Fish K. N., Nelson J. A. 1997; Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91:119–126 [CrossRef]
     [Google Scholar]
  30. Spencer J. V., Lockridge K. M., Barry P. A., Lin G., Tsang M., Penfold M. E., Schall T. J. 2002; Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J Virol 76:1285–1292 [CrossRef]
     [Google Scholar]
  31. Tolosa E., Li W., Yasuda Y., Wienhold W., Denzin L. K., Lautwein A., Driessen C., Schnorrer P., Weber E. other authors 2003; Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis. J Clin Invest 112:517–526 [CrossRef]
     [Google Scholar]
  32. Tomazin R., Boname J., Hegde N. R., Lewinsohn D. M., Altschuler Y., Jones T. R., Cresswell P., Nelson J. A., Riddell S. R., Johnson D. C. 1999; Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells. Nat Med 5:1039–1043 [CrossRef]
     [Google Scholar]
  33. Trombetta E. S., Mellman I. 2005; Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol 23:975–1028 [CrossRef]
     [Google Scholar]
  34. Watts C. 2004; The exogenous pathway for antigen presentation on major histocompatibility complex class II and CD1 molecules. Nat Immunol 5:685–692
     [Google Scholar]
  35. Ziegler A., Heinig J., Müller C., Götz H., Thinnes F. P., Uchanska-Ziegler B., Wernet P. 1986; Analysis by sequential immunoprecipitations of the specificities of the monoclonal antibodies TU22,34,35,36,37,39,43,58 and YD1/63.HLK directed against human HLA class II antigens. Immunobiology 171:77–92 [CrossRef]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.2008/001610-0
Loading
Human cytomegalovirus infection interferes with major histocompatibility complex type II maturation and endocytic proteases in dendritic cells at multiple levels
J. Gen. Virol. 89, 2427 (2008); https://doi.org/10.1099/vir.0.2008/001610-0
/content/journal/jgv/10.1099/vir.0.2008/001610-0
/content/journal/jgv/10.1099/vir.0.2008/001610-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error