Human Tregs convert latent TGF-β1, which is linked to the transmembrane protein GARP, into active, immunosuppressive TGF-β1. Stockis et al. show that this activation is mediated by integrin αVβ8, which is upregulated in activated Treg cells and forms a complex with GARP/latent TGF-β1. In vitro, antibodies used to block αV or β8 prevented TGF-β1 activation, and in a murine graft-versus-host disease model, a β8-blocking antibody abrogated the immunosuppressive effects of transferred Tregs as effectively as GARP-blocking antibodies.
Human regulatory T cells (Tregs) suppress other T cells by converting the latent, inactive form of TGF-beta1 into active TGF-beta1. In Tregs, TGF-beta1 activation requires GARP, a transmembrane protein that binds and presents latent TGF-beta1 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-beta1 production. RGD-binding integrins were shown to activate TGF-beta1 in several non-T cell types. Here we show that alphaVbeta8 dimers are present on stimulated human Tregs but not in other T cells, and that antibodies against alphaV or beta8 subunits block TGF-beta1 activation in vitro. We also show that alphaV and beta8 interact with GARP/latent TGF-beta1 complexes in human Tregs. Finally, a blocking antibody against beta8 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-beta1 activation on the surface of human Tregs implies an interaction between the integrin alphaVbeta8 and GARP/latent TGF-beta1 complexes. Immunosuppression by human Tregs can be inhibited by antibodies against GARP or against the integrin beta8 subunit. Such antibodies may prove beneficial against cancer or chronic infections.
Author Info: (1) de Duve Institute, Universite catholique de Louvain, B-1200 Brussels, Belgium. (2) de Duve Institute, Universite catholique de Louvain, B-1200 Brussels, Belgium. (3) Ludwig Ins
Author Info: (1) de Duve Institute, Universite catholique de Louvain, B-1200 Brussels, Belgium. (2) de Duve Institute, Universite catholique de Louvain, B-1200 Brussels, Belgium. (3) Ludwig Institute for Cancer Research, Brussels branch, B-1200 Brussels, Belgium. (4) de Duve Institute, Universite catholique de Louvain, B-1200 Brussels, Belgium. (5) Department of Pathology, University of California, San Francisco, CA 94110. (6) Department of Medicine, University of California, San Francisco, CA 94143. (7) de Duve Institute, Universite catholique de Louvain, B-1200 Brussels, Belgium. (8) de Duve Institute, Universite catholique de Louvain, B-1200 Brussels, Belgium; sophie.lucas@uclouvain.be.
