Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells

• Published in: Science (American Association for the Advancement of Science) Vol. 362; no. 6417; pp. 952 - 956
• Main Authors: Liénart, Stéphanie, Merceron, Romain, Vanderaa, Christophe, Lambert, Fanny, Colau, Didier, Stockis, Julie, van der Woning, Bas, De Haard, Hans, Saunders, Michael, Coulie, Pierre G, Savvides, Savvas N, Lucas, Sophie
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 23.11.2018
• Subjects: Cancer; Cancer immunotherapy; Cell activation; Cell surface; Crystal structure; Cytokines; Disulfide bonds; Glycoproteins; Growth factors; Humans; Immune system; Immune Tolerance; Immunity; Immunoregulation; Immunosuppression; Immunotherapy; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Medical treatment; Membrane Proteins - chemistry; Membrane Proteins - immunology; Monoclonal antibodies; Protein Conformation, beta-Strand; Protein Folding; Proteins; T-Lymphocytes, Regulatory - immunology; Transforming growth factor; Transforming Growth Factor beta1 - chemistry; Transforming Growth Factor beta1 - immunology; Transforming growth factor-b1
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aau2909

Transforming growth factor-β1 (TGF-β1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (T ) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP (glycoprotein A repetitions predominant) to integrin αVβ8 on their surface. We solved the crystal structure of GARP:latent TGF-β1 bound to an antibody that stabilizes the complex and blocks release of active TGF-β1. This finding reveals how GARP exploits an unusual medley of interactions, including fold complementation by the amino terminus of TGF-β1, to chaperone and orient the cytokine for binding and activation by αVβ8. Thus, this work further elucidates the mechanism of antibody-mediated blockade of TGF-β1 activation and immunosuppression by T .