A specific CD4 epitope bound by tregalizumab mediates activation of regulatory T cells by a unique signaling pathway

Immunol Cell Biol. 2015 Apr;93(4):396-405. doi: 10.1038/icb.2014.102. Epub 2014 Dec 16.

Abstract

CD4(+)CD25(+) regulatory T cells (Tregs) represent a specialized subpopulation of T cells, which are essential for maintaining peripheral tolerance and preventing autoimmunity. The immunomodulatory effects of Tregs depend on their activation status. Here we show that, in contrast to conventional anti-CD4 monoclonal antibodies (mAbs), the humanized CD4-specific monoclonal antibody tregalizumab (BT-061) is able to selectively activate the suppressive properties of Tregs in vitro. BT-061 activates Tregs by binding to CD4 and activation of signaling downstream pathways. The specific functionality of BT-061 may be explained by the recognition of a unique, conformational epitope on domain 2 of the CD4 molecule that is not recognized by other anti-CD4 mAbs. We found that, due to this special epitope binding, BT-061 induces a unique phosphorylation of T-cell receptor complex-associated signaling molecules. This is sufficient to activate the function of Tregs without activating effector T cells. Furthermore, BT-061 does not induce the release of pro-inflammatory cytokines. These results demonstrate that BT-061 stimulation via the CD4 receptor is able to induce T-cell receptor-independent activation of Tregs. Selective activation of Tregs via CD4 is a promising approach for the treatment of autoimmune diseases where insufficient Treg activity has been described. Clinical investigation of this new approach is currently ongoing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • CD4 Antigens / metabolism*
  • Cells, Cultured
  • Crystallography, X-Ray
  • Epitopes, B-Lymphocyte / metabolism*
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphocyte Activation
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Conformation
  • Signal Transduction
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • BT-061
  • CD4 Antigens
  • Epitopes, B-Lymphocyte
  • Immunosuppressive Agents
  • Interleukin-2 Receptor alpha Subunit
  • Transforming Growth Factor beta