Brief treatment with a highly selective immunoproteasome inhibitor promotes long-term cardiac allograft acceptance in mice

Proc Natl Acad Sci U S A. 2016 Dec 27;113(52):E8425-E8432. doi: 10.1073/pnas.1618548114. Epub 2016 Dec 12.


Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving autoimmunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit β5i that has thousands-fold selectivity over constitutive β5c. DPLG3 suppressed cytokine release from blood mononuclear cells and the activation of DCs and T cells, diminished accumulation of effector T cells, promoted expression of exhaustion and coinhibitory markers on T cells, and synergized with CTLA4-Ig to promote long-term acceptance of cardiac allografts across a major histocompatibility barrier. These findings demonstrate the potential value of using brief posttransplant immunoproteasome inhibition to entrain a long-term response favorable to allograft survival as part of an immunomodulatory regimen that is neither broadly immunosuppressive nor toxic.

Keywords: T-cell exhaustion; allograft; effector T cells; immunoproteasome; memory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Graft Survival*
  • Heart Transplantation / methods*
  • Hep G2 Cells
  • Humans
  • Immunologic Memory
  • Immunosuppressive Agents / pharmacology*
  • Leukocytes, Mononuclear / cytology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology*
  • T-Lymphocytes / immunology


  • Cytokines
  • Immunosuppressive Agents
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex