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MHC Class II Ubiquitination Regulates Dendritic Cell Function and Immunity

Kayla R. Wilson, Devi Jenika, Annabelle B. Blum, Christophe Macri, Bangyan Xu, Haiyin Liu, Patrick Schriek, Dominik Schienstock, Lauren Francis, F. Victor Makota, Satoshi Ishido, Scott N. Mueller, Mireille H. Lahoud, Irina Caminschi, Laura E. Edgington-Mitchell, Jose A. Villadangos and Justine D. Mintern
J Immunol November 1, 2021, 207 (9) 2255-2264; DOI: https://doi.org/10.4049/jimmunol.2001426
Kayla R. Wilson
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Devi Jenika
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Annabelle B. Blum
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Christophe Macri
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Bangyan Xu
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Haiyin Liu
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Patrick Schriek
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Dominik Schienstock
†Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia;
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Lauren Francis
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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F. Victor Makota
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Satoshi Ishido
‡Department of Microbiology, Hyogo College of Medicine, Nishinomiya, Japan;
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Scott N. Mueller
†Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia;
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Mireille H. Lahoud
§Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia;
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Irina Caminschi
†Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia;
§Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia;
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Laura E. Edgington-Mitchell
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
¶Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia;
‖Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, Bluestone Center for Clinical Research, New York, NY; and
#Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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Jose A. Villadangos
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
†Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia;
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Justine D. Mintern
*Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia;
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Key Points

  • MHC II ubiquitination impacts dendritic cell numbers and phenotype.

  • MHC II ubiquitination is critical for Ag-dependent T cell responses in vivo.

  • MHC II ubiquitination is required for Ab responses.

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Abstract

MHC class II (MHC II) Ag presentation by dendritic cells (DCs) is critical for CD4+ T cell immunity. Cell surface levels of MHC II loaded with peptide is controlled by ubiquitination. In this study, we have examined how MHC II ubiquitination impacts immunity using MHC IIKRKI/KI mice expressing mutant MHC II molecules that are unable to be ubiquitinated. Numbers of conventional DC (cDC) 1, cDC2 and plasmacytoid DCs were significantly reduced in MHC IIKRKI/KI spleen, with the remaining MHC IIKRKI/KI DCs expressing an altered surface phenotype. Whereas Ag uptake, endosomal pH, and cathepsin protease activity were unaltered, MHC IIKRKI/KI cDC1 produced increased inflammatory cytokines and possessed defects in Ag proteolysis. Immunization of MHC IIKRKI/KI mice identified impairments in MHC II and MHC class I presentation of soluble, cell-associated and/or DC-targeted OVA via mAb specific for DC surface receptor Clec9A (anti-Clec9A-OVA mAb). Reduced T cell responses and impaired CTL killing was observed in MHC IIKRKI/KI mice following immunization with cell-associated and anti-Clec9A-OVA. Immunization of MHC IIKRKI/KI mice failed to elicit follicular Th cell responses and generated barely detectable Ab to anti-Clec9A mAb-targeted Ag. In summary, MHC II ubiquitination in DCs impacts the homeostasis, phenotype, cytokine production, and Ag proteolysis by DCs with consequences for Ag presentation and T cell and Ab-mediated immunity.

Footnotes

  • This work was supported by Department of Health Australia, National Health and Medical Research Council grants or fellowships 1058193, 1113293, 1154502, and 1163090 (to J.A.V.) and 1161101 and 1129672 (to J.D.M.), Department of Education and Training, Australian Research Council (ARC) grants or fellowships 160103134, 170102471, and 190102213 to J.A.V. and 190101242, 180100844, 160101373, and 180100521 (to J.D.M.), a Human Frontiers Science Program grant (0064/2011 to J.A.V.), and the Australian Government’s National Health and Medical Research Council Victorian State Government Operational Infrastructure Support and the Independent Research Institutes Infrastructure Support Scheme. L.E.E.-M. was supported by the Russell and Mab Grimwade Miegunyah Fund, funded at the University of Melbourne, which supplied a Grimwade Fellowship, and an ARC Discovery Early Career Researcher Award Fellowship (ARC, DE180100418).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    BMDC
    bone marrow–derived DC
    cDC
    conventional DC
    CTV
    CellTrace Violet
    CTVhi
    splenocytes pulsed with OVA257–264 and labeled with a high concentration of CTV
    CTVlo
    splenocytes labeled with a low concentration of CTV
    DC
    dendritic cell
    gMFI
    geometric mean fluorescence intensity
    MARCH
    membrane-associated RING-CH-type finger
    MHC I
    MHC class I
    MHC II
    MHC class II
    pMHC II
    peptide-loaded MHC II
    TFH
    T follicular helper
    WT
    wild-type

  • Received December 18, 2020.
  • Accepted August 17, 2021.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 207 (9)
The Journal of Immunology
Vol. 207, Issue 9
1 Nov 2021
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MHC Class II Ubiquitination Regulates Dendritic Cell Function and Immunity
Kayla R. Wilson, Devi Jenika, Annabelle B. Blum, Christophe Macri, Bangyan Xu, Haiyin Liu, Patrick Schriek, Dominik Schienstock, Lauren Francis, F. Victor Makota, Satoshi Ishido, Scott N. Mueller, Mireille H. Lahoud, Irina Caminschi, Laura E. Edgington-Mitchell, Jose A. Villadangos, Justine D. Mintern
The Journal of Immunology November 1, 2021, 207 (9) 2255-2264; DOI: 10.4049/jimmunol.2001426

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MHC Class II Ubiquitination Regulates Dendritic Cell Function and Immunity
Kayla R. Wilson, Devi Jenika, Annabelle B. Blum, Christophe Macri, Bangyan Xu, Haiyin Liu, Patrick Schriek, Dominik Schienstock, Lauren Francis, F. Victor Makota, Satoshi Ishido, Scott N. Mueller, Mireille H. Lahoud, Irina Caminschi, Laura E. Edgington-Mitchell, Jose A. Villadangos, Justine D. Mintern
The Journal of Immunology November 1, 2021, 207 (9) 2255-2264; DOI: 10.4049/jimmunol.2001426
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