RGMB enhances the suppressive activity of the monomeric secreted form of CTLA-4

Sci Rep. 2019 May 6;9(1):6984. doi: 10.1038/s41598-019-43068-y.


The immunoregulatory molecule CTLA-4 plays a crucial role in the maintenance of immune homeostasis. CTLA-4-neutralizing antibodies are now approved for the treatment of advanced melanoma, and are in development for treating other cancers as well. However, a thorough understanding of CTLA-4 function at the molecular level is necessary in order to develop strategies to prevent the unintended autoimmunity that is frequently associated with systemic blockade of CTLA-4 activity. Here, we describe an extracellular molecule, repulsive guidance molecule B (RGMB) as a novel binding partner of CTLA-4. RGMB expression was detected at high levels in dendritic cell subsets that have been suggested to have tolerogenic capabilities. RGMB binds an extracellular domain of CTLA-4, and specifically strengthens the binding of the monomeric, soluble form of CTLA-4 (sCTLA-4) to CD80, enhancing CTLA-4's suppressive effect on co-stimulation. Examination of expression data from tumor tissues revealed a negative correlation between RGMB expression and immune activation status in the majority of non-hematologic tumor tissues. These findings advance our understanding of CTLA-4 activity, as well as identify the RGMB/CTLA-4 binding interface as a potential target for the development of novel immune checkpoint blockade therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • Binding Sites
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / genetics*
  • CTLA-4 Antigen / immunology
  • CTLA-4 Antigen / metabolism
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Cell Adhesion Molecules, Neuronal / immunology
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cloning, Molecular
  • Databases, Genetic
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / immunology*
  • Gene Library
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • HEK293 Cells
  • Humans
  • Immune Tolerance
  • Jurkat Cells
  • Lymphocyte Activation
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Two-Hybrid System Techniques


  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cell Adhesion Molecules, Neuronal
  • RGMB protein, human
  • Recombinant Proteins