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

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Science  23 Nov 2018:
Vol. 362, Issue 6417, pp. 952-956
DOI: 10.1126/science.aau2909

Visualizing TGF-β1 regulation by GARP

Regulatory 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. 952


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.

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