Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells
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 presen...
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| Published in | Science (American Association for the Advancement of Science) Vol. 362; no. 6417; pp. 952 - 956 |
|---|---|
| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The American Association for the Advancement of Science
23.11.2018
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| Subjects | |
| Online Access | Get full text |
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| Abstract | 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
. |
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| AbstractList | Visualizing TGF-β1 regulation by GARPRegulatory T cells (Tregs) can suppress immune responses through a variety of mechanisms. One such mechanism involves the activation of a surface-bound latent form of the cytokine transforming growth factor–β1 (TGF-β1). Within the cell, newly synthesized pro-TGF-β1 homodimers form disulfide bonds with the transmembrane protein GARP, which acts to chaperone and orient the cytokine for activation at the cell surface. Liénart et al. reveal how GARP interacts with TGF-β1, using a crystal structure in which the complex was stabilized using a Fab fragment from a monoclonal antibody (MHG-8) that binds to the complex. In so doing, they also demonstrate how MHG-8 prevents membrane-associated TGF-β1 release. These structural and mechanistic insights may inform treatments of diseases with altered TGF-β1 functionality and dysfunctional Treg activity, including cancer immunotherapy.Science, this issue p. 952Transforming 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 (Tregs) 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 Tregs. Visualizing TGF-β1 regulation by GARP Regulatory T cells (T regs ) can suppress immune responses through a variety of mechanisms. One such mechanism involves the activation of a surface-bound latent form of the cytokine transforming growth factor–β1 (TGF-β1). Within the cell, newly synthesized pro-TGF-β1 homodimers form disulfide bonds with the transmembrane protein GARP, which acts to chaperone and orient the cytokine for activation at the cell surface. Liénart et al. reveal how GARP interacts with TGF-β1, using a crystal structure in which the complex was stabilized using a Fab fragment from a monoclonal antibody (MHG-8) that binds to the complex. In so doing, they also demonstrate how MHG-8 prevents membrane-associated TGF-β1 release. These structural and mechanistic insights may inform treatments of diseases with altered TGF-β1 functionality and dysfunctional T reg activity, including cancer immunotherapy. Science , this issue p. 952 A crystal structure elucidates the mechanism of antibody-mediated blockade of TGF-β1 activation and immunosuppression by regulatory T cells. 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 regs ) 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 regs . 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 . 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 (Tregs) 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 Tregs. |
| Author | Lambert, Fanny van der Woning, Bas Saunders, Michael Lucas, Sophie Vanderaa, Christophe Stockis, Julie Coulie, Pierre G Liénart, Stéphanie Merceron, Romain Savvides, Savvas N Colau, Didier De Haard, Hans |
| Author_xml | – sequence: 1 givenname: Stéphanie orcidid: 0000-0002-5825-6979 surname: Liénart fullname: Liénart, Stéphanie organization: de Duve Institute, UCLouvain, 1200 Brussels, Belgium – sequence: 2 givenname: Romain surname: Merceron fullname: Merceron, Romain organization: VIB Center for Inflammation Research, 9052 Ghent, Belgium – sequence: 3 givenname: Christophe orcidid: 0000-0001-7443-5427 surname: Vanderaa fullname: Vanderaa, Christophe organization: de Duve Institute, UCLouvain, 1200 Brussels, Belgium – sequence: 4 givenname: Fanny surname: Lambert fullname: Lambert, Fanny organization: de Duve Institute, UCLouvain, 1200 Brussels, Belgium – sequence: 5 givenname: Didier surname: Colau fullname: Colau, Didier organization: Ludwig Cancer Research, Brussels, Belgium – sequence: 6 givenname: Julie orcidid: 0000-0003-4911-6891 surname: Stockis fullname: Stockis, Julie organization: Walloon Excellence in Lifesciences and Biotechnology, 1300 Wavre, Belgium – sequence: 7 givenname: Bas surname: van der Woning fullname: van der Woning, Bas organization: argenx, 9052 Zwijnaarde, Belgium – sequence: 8 givenname: Hans surname: De Haard fullname: De Haard, Hans organization: argenx, 9052 Zwijnaarde, Belgium – sequence: 9 givenname: Michael surname: Saunders fullname: Saunders, Michael organization: argenx, 9052 Zwijnaarde, Belgium – sequence: 10 givenname: Pierre G surname: Coulie fullname: Coulie, Pierre G organization: Walloon Excellence in Lifesciences and Biotechnology, 1300 Wavre, Belgium – sequence: 11 givenname: Savvas N orcidid: 0000-0003-3420-5947 surname: Savvides fullname: Savvides, Savvas N email: sophie.lucas@uclouvain.be, savvas.savvides@ugent.be organization: VIB Center for Inflammation Research, 9052 Ghent, Belgium – sequence: 12 givenname: Sophie orcidid: 0000-0003-1287-7996 surname: Lucas fullname: Lucas, Sophie email: sophie.lucas@uclouvain.be, savvas.savvides@ugent.be organization: Walloon Excellence in Lifesciences and Biotechnology, 1300 Wavre, Belgium |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30361387$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works |
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| Snippet | 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... Visualizing TGF-β1 regulation by GARP Regulatory T cells (T regs ) can suppress immune responses through a variety of mechanisms. One such mechanism involves... Visualizing TGF-β1 regulation by GARPRegulatory T cells (Tregs) can suppress immune responses through a variety of mechanisms. One such mechanism involves the... |
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| SubjectTerms | 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 |
| Title | Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/30361387 https://www.proquest.com/docview/2138186396/abstract/ https://search.proquest.com/docview/2126910209 |
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