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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

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Abstract

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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Acknowledgements

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OVA; L. Brown (University of Melbourne, Australia) for the influenza strain A/PR/8/34; P. Benaroch for sharing unpublished information and critically reading the manuscript; and D. John, F. Kupresanin and all members of the Flow Cytometry and Animal Services facilities at The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.).

Affiliations

  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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Contributions

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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DOI

https://doi.org/10.1038/ni.1665

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