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

• Published in: Scientific reports 2019-05, Vol.9 (1), p.6984, Article 6984
• Main Authors: Sekiya, Takashi, Takaki, Satoshi
• Format: Article
• Language: English
• Subjects: 13/109; 13/21; 38/77; 631/250/2161; 631/250/38; 82/83; 96; Antibodies; Antigens; Autoimmunity; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Binding Sites; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD80 antigen; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - immunology; Cell Adhesion Molecules, Neuronal - metabolism; Cloning, Molecular; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; CTLA-4 Antigen - metabolism; CTLA-4 protein; Databases, Genetic; Dendritic cells; 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; Hepatitis; Homeostasis; Humanities and Social Sciences; Humans; Immune checkpoint; Immune response; Immune Tolerance; Immunology; Immunoregulation; Jurkat Cells; Ligands; Lymphocyte Activation; Lymphocytes; Melanoma; multidisciplinary; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Protein Binding; Protein Interaction Domains and Motifs; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Two-Hybrid System Techniques
• ISSN: 2045-2322; 2045-2322
• 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.