Blocking immunosuppression by human Tregs with antibodies against GArP/latent TGF-β1 complexes

Production of active TGF-β is regulated at a post-translational level and implies the release of the mature cytokine from the inactive latent TGF-β precursor. Several cell-type specific mechanisms of TGF-β activation have been described. In this thesis, we identified that TGF-β1 activation by regulatory T cells (Tregs) implies the transmembrane protein GARP, which binds and presents latent TGF-β1 at the Tregs cell surface. We derived two monoclonal antibodies directed against the GARP/latent TGF-β1 complex and blocking TGF-β1 activation and immunosuppression by human Tregs. The crystal structure of the GARP/latent TGF-β1 complex bound by one blocking antibody reveals how GARP presents latent TGF-β1 for activation at the Treg cell surface and how blocking anti-GARP/latent TGF-β1 antibodies inhibit TGF-β1 activation by human Tregs. These antibodies may serve as therapeutic tools to improve efficiency of cancer immunotherapy.