Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin αVβ8

Human regulatory T cells (Tregs) suppress other T cells by converting the latent, inactive form of TGF-beta 1 into active TGF-beta 1. In Tregs, TGF-beta 1 activation requires GARP, a transmembrane protein that binds and presents latent TGF-beta 1 on the surface of Tregs stimulated through their T cell receptor. However, GARP is not sufficient because transduction of GARP in non-Treg T cells does not induce active TGF-beta 1 production. RGD-binding integrins were shown to activate TGF-beta 1 in several non-T cell types. Here we show that alpha V beta 8 dimers are present on stimulated human Tregs but not in other T cells, and that antibodies against alpha V or beta 8 subunits block TGF-beta 1 activation in vitro. We also show that alpha V and beta 8 interact with GARP/latent TGF-beta 1 complexes in human Tregs. Finally, a blocking antibody against beta 8 inhibited immunosuppression by human Tregs in a model of xenogeneic graft-vs.-host disease induced by the transfer of human T cells in immunodeficient mice. These results show that TGF-beta 1 activation on the surface of human Tregs implies an interaction between the integrin alpha V beta 8 and GARP/latent TGF-beta 1 complexes. Immunosuppression by human Tregs can be inhibited by antibodies against GARP or against the integrin beta 8 subunit. Such antibodies may prove beneficial against cancer or chronic infections.