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Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells

Nature Immunology volume 9, pages 12441252 (2008) | Download Citation



The importance of conventional dendritic cells (cDCs) in the processing and presentation of antigen is well established, but the contribution of plasmacytoid dendritic cells (pDCs) to these processes, and hence to T cell immunity, remains unclear. Here we showed that unlike cDCs, pDCs continued to synthesize major histocompatibility complex (MHC) class II molecules and the MHC class II ubiquitin ligase MARCH1 long after activation. Sustained MHC class II–peptide complex formation, ubiquitination and turnover rendered pDCs inefficient in the presentation of exogenous antigens but enabled pDCs to continuously present endogenous viral antigens in their activated state. As the antigen-presenting abilities of cDCs and pDCs are fundamentally distinct, these two cell types may activate largely nonoverlapping repertoires of CD4+ T cells.

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  1. 1.

    , & Control of MHC class II antigen presentation in dendritic cells: a balance between creative and destructive forces. Immunol. Rev. 207, 191–205 (2005).

  2. 2.

    & Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7, 19–30 (2007).

  3. 3.

    & Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat. Rev. Immunol. 7, 543–555 (2007).

  4. 4.

    et al. Inhibition of MHC class II expression and immune responses by c-MIR. J. Immunol. 177, 341–354 (2006).

  5. 5.

    et al. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature 444, 115–118 (2006).

  6. 6.

    et al. Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity 25, 885–894 (2006).

  7. 7.

    et al. Novel regulation of MHC class II function in B cells. EMBO J. 26, 846–854 (2007).

  8. 8.

    et al. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. Proc. Natl. Acad. Sci. USA 105, 3491–3496 (2008).

  9. 9.

    et al. Interleukin-10-induced MARCH1 mediates intracellular sequestration of MHC class II in monocytes. Eur. J. Immunol. 38, 1225–1230 (2008).

  10. 10.

    et al. A novel family of membrane-bound E3 ubiquitin ligases. J. Biochem. 140, 147–154 (2006).

  11. 11.

    et al. Presentation of exogenous protein antigens by dendritic cells to T cell clones. Intact protein is presented best by immature, epidermal Langerhans cells. J. Exp. Med. 169, 1169–1178 (1989).

  12. 12.

    et al. Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens. Proc. Natl. Acad. Sci. USA 104, 17753–17758 (2007).

  13. 13.

    , & Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5, 1219–1226 (2004).

  14. 14.

    IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005).

  15. 15.

    , & Development of a novel transgenic mouse for the study of interactions between CD4 and CD8 T cells during graft rejection. Am. J. Transplant. 3, 1355–1362 (2003).

  16. 16.

    et al. Distinct roles for the NF-κB1 and c-Rel transcription factors in the differentiation and survival of plasmacytoid and conventional dendritic cells activated by TLR-9 signals. Blood 106, 3457–3464 (2005).

  17. 17.

    , , , & , Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307, 1630–1634 (2005).

  18. 18.

    , , , & MHC class II expression is differentially regulated in plasmacytoid and conventional dendritic cells. Nat. Immunol. 5, 899–908 (2004).

  19. 19.

    & MHC class II structure, occupancy and surface expression determined by post-endoplasmic reticulum antigen binding. Nature 353, 134–139 (1991).

  20. 20.

    et al. The protease inhibitor cystatin C is differentially expressed among dendritic cell populations, but does not control antigen presentation. J. Immunol. 171, 5003–5011 (2003).

  21. 21.

    , & Dendritic cells constitutively present self antigens in their immature state in vivo, and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis. Blood 103, 2187–2195 (2004).

  22. 22.

    , , , & Characterization and quantitation of peptide-MHC complexes produced from hen egg lysozyme using a monoclonal antibody. Immunity 6, 727–738 (1997).

  23. 23.

    et al. Activation of influenza virus-specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity. Blood 101, 3520–3526 (2003).

  24. 24.

    et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200, 89–98 (2004).

  25. 25.

    , , , & CpG-matured murine plasmacytoid dendritic cells are capable of in vivo priming of functional CD8 T cell responses to endogenous but not exogenous antigens. J. Exp. Med. 199, 567–579 (2004).

  26. 26.

    et al. Tumor antigen processing and presentation depend critically on dendritic cell type and the mode of antigen delivery. Blood 105, 2465–2472 (2005).

  27. 27.

    et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat. Immunol. 7, 652–662 (2006).

  28. 28.

    et al. Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors. Blood 107, 3600–3608 (2006).

  29. 29.

    et al. Organ-dependent in vivo priming of naive CD4+, but not CD8+, T cells by plasmacytoid dendritic cells. J. Exp. Med. 204, 1923–1933 (2007).

  30. 30.

    et al. Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-α production. Blood 111, 4245–4253 (2008).

  31. 31.

    et al. Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity. Nat. Immunol. 7, 165–172 (2006).

  32. 32.

    Helping the CD8+ T-cell response. Nat. Rev. Immunol. 4, 595–602 (2004).

  33. 33.

    et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93 (2005).

  34. 34.

    et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b but not plasmacytoid dendritic cells. J. Exp. Med. 205, 1621–1634 (2008).

  35. 35.

    , , & Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

  36. 36.

    et al. A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity. Immunity 1, 73–83 (1994).

  37. 37.

    et al. CD8+ T cell-mediated spontaneous diabetes in neonatal mice. J. Immunol. 157, 978–983 (1996).

  38. 38.

    et al. Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc. Natl. Acad. Sci. USA 96, 14943–14948 (1999).

  39. 39.

    et al. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood 102, 2187–2194 (2003).

  40. 40.

    , , , & CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J. Immunol. 164, 2978–2986 (2000).

  41. 41.

    et al. Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8+ dendritic cells only after microbial stimulus. J. Exp. Med. 196, 1307–1319 (2002).

  42. 42.

    et al. Cutting edge: generation of splenic CD8+ and CD8 dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures. J. Immunol. 174, 6592–6597 (2005).

  43. 43.

    , , & The impact of H2-DM on humoral immune responses. J. Immunol. 167, 6348–6355 (2001).

  44. 44.

    , , , & Degradation of mouse invariant chain: roles of cathepsins S and D and the influence of major histocompatibility complex polymorphism. J. Exp. Med. 186, 549–560 (1997).

  45. 45.

    , & Selective modulation of the major histocompatibility complex class II antigen presentation pathway following B cell receptor ligation and protein kinase C activation. J. Biol. Chem. 272, 3641–3647 (1997).

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We thank E. Unanue (Washington University) and R. Gugasyan (the Walter and Eliza Hall Institute) for antibody Aw3.18; M. Jenkins (University of Minnesota Medical School) for act-mOVA mice; E. Maraskovsky (CSL) for Alexa Fluor 488–conjugated OVA; L. Brown (University of Melbourne, Australia) for the influenza strain A/PR/8/34; P. Benaroch for sharing unpublished information and critically reading the manuscript; and D. John, F. Kupresanin and all members of the Flow Cytometry and Animal Services facilities at The Walter and Eliza Hall Institute of Medical Research for technical assistance. Supported by the National Health and Medical Research Council of Australia (G.T.B., W.R.H. and J.A.V.), the Anti-Cancer Council of Australia (J.A.V.), the Gottlieb Daimler and Karl Benz Foundation (P.S.), the Wellcome Trust (G.T.B.), the Howard Hughes Medical Institute (G.T.B. and W.R.H.), the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.I.), the Japan Society for the Promotion of Science (S.I.), the University of Melbourne (L.J.Y., N.S.W. and A.M.M.) and the Leukemia and Lymphoma Society (J.A.V.).

Author information

Author notes

    • Nicholas S Wilson
    • , Petra Schnorrer
    •  & Meredith O'Keeffe

    Present address: Department of Molecular Oncology, Genentech, California 94080, USA (N.S.W.); Division of Molecular Immunology, German Cancer Research Centre, D-69120 Heidelberg, Germany (P.S.); Bavarian-Nordic, Martinsried 82152, Germany (M.O.); Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3050, Australia (W.R.H.).


  1. The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville, Victoria 3050, Australia.

    • Louise J Young
    • , Nicholas S Wilson
    • , Petra Schnorrer
    • , Anna Proietto
    • , Adele M Mount
    • , Gabrielle T Belz
    • , Meredith O'Keeffe
    • , William R Heath
    • , Ken Shortman
    •  & Jose A Villadangos
  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.

    • Louise J Young
    • , Nicholas S Wilson
    • , Anna Proietto
    • , Adele M Mount
    • , William R Heath
    •  & Jose A Villadangos
  3. The Cooperative Research Centre for Vaccine Technology, Parkville, Victoria 3050, Australia.

    • Nicholas S Wilson
    • , Gabrielle T Belz
    • , William R Heath
    •  & Jose A Villadangos
  4. Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, NL-3508 TD, The Netherlands.

    • Toine ten Broeke
    •  & Willem Stoorvogel
  5. Laboratory for Infectious Immunity, RIKEN Research Center for Allergy and Immunology, Yokohama, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045 Japan.

    • Yohei Matsuki
    • , Mari Ohmura-Hoshino
    •  & Satoshi Ishido


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L.J.Y. designed and did most experiments and wrote the manuscript; N.S.W. designed and did many of the initial observations and experiments; P.S. did the assessments of OVA uptake and degradation; A.P. did the analyses of March1-deficient DCs and helped with the real-time PCR studies; T.t.B. did the ubiquitination analyses; Y.M., M.O.-H. and S.I. provided MARCH1-deficient mice and helped design the analyses of DCs from these mice; A.M.M. and G.T.B. provided reagents and help in the experiments involving influenza virus; M.O.'K. helped to design experiments, W.S. designed the analyses of ubiquitination; W.R.H. and K.S. assisted with the design of the study and interpretation of results and provided mice and reagents, J.A.V. designed and supervised the study and wrote the manuscript; and all authors discussed the results and contributed to writing the manuscript.

Corresponding author

Correspondence to Jose A Villadangos.

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