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Frontiers In Immunology

Publication date: 2021-04-21
Volume: 12
Publisher: Frontiers Media

Author:

Claeys, Elisa
Pauwels, Eva ; Humblet-Baron, Stephanie ; Provinciael, Becky ; Schols, Dominique ; Waer, Mark ; Sprangers, Ben ; Vermeire, Kurt

Keywords:

cyclotriazadisulfonamide (CADA), CD4 receptor, T cell activation, immunosuppression, 4-1BB (CD137), signal peptide, ER, co-translational translocation, Science & Technology, Life Sciences & Biomedicine, Immunology, cyclotriazadisulfonamide (CADA), CD4 receptor, T cell activation, immunosuppression, 4-1BB (CD137), signal peptide, ER, co-translational translocation, CELL-SURFACE, SIGNALS, CD4 Antigens, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Proliferation, Cells, Cultured, Cytokines, Endoplasmic Reticulum, HEK293 Cells, Humans, Jurkat Cells, Leukocytes, Mononuclear, Lymphocyte Activation, Protein Transport, STAT5 Transcription Factor, Small Molecule Libraries, Sulfonamides, Tumor Necrosis Factor Receptor Superfamily, Member 9, Up-Regulation, 1107 Immunology, 1108 Medical Microbiology, 3101 Biochemistry and cell biology, 3105 Genetics, 3204 Immunology

Abstract:

The small molecule cyclotriazadisulfonamide (CADA) down-modulates the human CD4 receptor, an important factor in T cell activation. Here, we addressed the immunosuppressive potential of CADA using different activation models. CADA inhibited lymphocyte proliferation with low cellular toxicity in a mixed lymphocyte reaction, and when human PBMCs were stimulated with CD3/CD28 beads, phytohemagglutinin or anti-CD3 antibodies. The immunosuppressive effect of CADA involved both CD4+ and CD8+ T cells but was, surprisingly, most prominent in the CD8+ T cell subpopulation where it inhibited cell-mediated lympholysis. Immunosuppression by CADA was characterized by suppressed secretion of various cytokines, and reduced CD25, phosphoSTAT5 and CTPS-1 levels. We discovered a direct down-modulatory effect of CADA on 4-1BB (CD137) expression, a survival factor for activated CD8+ T cells. More specifically, CADA blocked 4‑1BB protein biosynthesis by inhibition of its co-translational translocation into the ER in a signal peptide-dependent way. Taken together, this study demonstrates that CADA, as potent down-modulator of human CD4 and 4‑1BB receptor, has promising immunomodulatory characteristics. This would open up new avenues toward chemotherapeutics that act as selective protein down-modulators to treat various human immunological disorders.