Structural basis of latent TGF-beta 1 presentation and activation by GARP on human regulatory T cells

Transforming growth factor-beta 1 (TGF-beta 1) 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-beta 1 presented by GARP (glycoprotein A repetitions predominant) to integrin alpha V beta 8 on their surface. We solved the crystal structure of GARP: latent TGF-beta 1 bound to an antibody that stabilizes the complex and blocks release of active TGF-beta 1. This finding reveals how GARP exploits an unusual medley of interactions, including fold complementation by the amino terminus of TGF-beta 1, to chaperone and orient the cytokine for binding and activation by alpha V beta 8. Thus, this work further elucidates the mechanism of antibody-mediated blockade of TGF-beta 1 activation and immunosuppression by T-regs.