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Correlation of dendritic cell maturation and the formation of aggregates of poly-ubiquitinated proteins in the cytosol

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Abstract

Dendritic cells (DCs) are the most powerful antigen presenting cells (APCs) in the immune system. Therefore, they are able to take up antigen by phagocytosis, macropinocytosis or endocytosis, process it in the cytosol and present it to naive T cells. It is known that presentation of the immunodominant influenza virus nucleoprotein-derived CTL epitope is delayed in bone marrow-derived DCs (BMDCs) compared to non-professional APCs. This delay coincided with the formation of transient aggregations of ubiquitinated proteins (DALIS, dendritic cell aggresome-like induced structures), which contain probably defective ribosomal products (DRiPs). DRiPs appear in the cytosol of maturing DCs and macrophages. Normally, DRiPs are degraded rapidly by proteasomes. However, their storage in DALIS delays their degradation. So, it is hypothesized that DALIS can function as antigen depots allowing DCs to coordinate maturation and antigen presentation during their migration to the lymph nodes. Upon inhibition of several pathways among the in signal transduction pathways of DCs, like the phosphatidylinositol 3-kinase (PI3-K) or the mammalian target of Rapamycin (mTOR), the cells show a rendered maturation profile. The formation of DALIS is inhibited in these cells which can be expected to influence antigen processing and presentation.

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Abbreviations

BMDC:

Bone marrow-derived dendritic cell

CTL:

Cytotoxic T lymphocytes

DALIS:

Dendritic cell aggresome-like induced structures

DRiPs:

Defective ribosomal products

mCMV:

Murine cytomegalovirus

NP:

Nucleoprotein

PI3-K:

Phosphatidylinositol 3-kinase

mTOR:

Mammalian target of Rapamycin

TLR:

Toll-like receptor

LPS:

Lipopolysaccharid

References

  1. Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258

    Article  CAS  PubMed  Google Scholar 

  2. Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S (2002) Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 20:621–667

    Article  CAS  PubMed  Google Scholar 

  3. Lelouard H, Gatti E, Cappello F, Gresser O, Camosseto V, Pierre P (2002) Transient aggregation of ubiquitinated proteins during dendritic cell maturation. Nature 417:177–182

    Article  CAS  PubMed  Google Scholar 

  4. Canadien V, Tan T, Zilber R, Szeto J, Perrin AJ, Brumell JH (2005) Cutting edge: microbial products elicit formation of dendritic cell aggresome-like induced structures in macrophages. J Immunol 174:2471–2475

    Article  CAS  PubMed  Google Scholar 

  5. Herter S, Osterloh P, Hilf N, Rechtsteiner G, Hohfeld J, Rammensee HG, Schild H (2005) Dendritic cell aggresome-like-induced structure formation and delayed antigen presentation coincide in influenza virus-infected dendritic cells. J Immunol 175:891–898

    Article  CAS  PubMed  Google Scholar 

  6. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655

    Article  CAS  PubMed  Google Scholar 

  7. Reuben JS (2006) Ras, PI(3)K and mTOR signalling controls tumor cell growth. Nature 441:424–430

    Article  Google Scholar 

  8. Yewdell JW, Schubert U, Bennink JR (2001) At the crossroads of cell biology and immunology: DRiPs and other sources of peptide ligands for MHC class I molecules. J Cell Sci 114:845–851

    Article  CAS  PubMed  Google Scholar 

  9. Yewdell J (2002) To DRiP or not to DRiP: generating peptide ligands for MHC class I molecules from biosynthesized proteins. Mol Immunol 39:139–146

    Article  CAS  PubMed  Google Scholar 

  10. Yewdell JW, Anton LC, Bennink JR (1996) Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules? J Immunol 157:1823–1826

    Article  CAS  PubMed  Google Scholar 

  11. Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR (2000) Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404:770–774

    Article  CAS  PubMed  Google Scholar 

  12. Lelouard H, Ferrand V, Marguet D, Bania J, Camosseto V, David A, Gatti E, Pierre P (2004) Dendritic cell aggresome-like induced structures are dedicated areas for ubiquitination and storage of newly synthesized defective proteins. J Cell Biol 164:667–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bhattacharyya S, Sen P, Wallet M, Long B, Baldwin AS Jr., Tisch R (2004) Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IkappaB kinase activity. Blood 104:1100–1109

    Article  CAS  PubMed  Google Scholar 

  14. Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, Bernasconi S, Sironi M, Santoro A, Garlanda C, Facchetti F, Wymann MP, Vecchi A, Hirsch E, Mantovani A, Sozzani S (2004) Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-deficient mice. EMBO J 23:3505–3515

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ardeshna KM, Pizzey AR, Devereux S, Khwaja A (2000) The PI3 kinase, p38 SAP kinase, and NF-kappaB signal transduction pathways are involved in the survival and maturation of Lipopolysaccharide-stimulated human monocyte-derived dendritic cells. Blood 96:1039–1046

    Article  CAS  PubMed  Google Scholar 

  16. Hackstein H (2002) Rapamycin inhibits macropinocytosis and mannose receptor-mediated endocytosis by BMDC. Blood 100(3):1084

    Article  CAS  PubMed  Google Scholar 

  17. Morice WG (1993) Rapamycin inhibition of interleukin-2-dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes. J Biol Chem 268(30):22737–22745

    Article  CAS  PubMed  Google Scholar 

  18. Sehgal SN (1998) Rapamune® (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 31(5):335–340

    Article  CAS  PubMed  Google Scholar 

  19. Lelouard H (2007) Regulation of translation is required for dendritic cell function and survival during activation. JCB 179(7):1427–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Reddehase MJ (2002) Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Rev Immunol 2:831–844

    Article  CAS  PubMed  Google Scholar 

  21. Wagner M, Gutermann A, Podlech J, Reddehase MJ, Koszinowski UH (2002) Major histocompatibility complex class I allele-specific cooperative and competitive interactions between immune evasion proteins of cytomegalovirus. J Exp Med 196:805–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Institute for Immunology, Johannes Gutenberg-University, Hochhaus am Augustusplatz 1, 55131, Mainz, Germany

    Melanie Faßbender, Sylvia Herter & Hansjörg Schild

  2. Institute for Virology, Johannes Gutenberg-University, Mainz, Germany

    Rafaela Holtappels

Authors
  1. Melanie Faßbender
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  2. Sylvia Herter
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  3. Rafaela Holtappels
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  4. Hansjörg Schild
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Corresponding author

Correspondence to Hansjörg Schild.

Additional information

This work was supported by grants from the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 490, individual projects E6 to H.S. and E3 to R.H.).

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Faßbender, M., Herter, S., Holtappels, R. et al. Correlation of dendritic cell maturation and the formation of aggregates of poly-ubiquitinated proteins in the cytosol. Med Microbiol Immunol 197, 185–189 (2008). https://doi.org/10.1007/s00430-008-0091-4

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  • DOI: https://doi.org/10.1007/s00430-008-0091-4

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