Membrane protein GARP is a receptor for latent TGF-beta on the surface of activated human Treg.

Human regulatory T cell (Treg) and T helper (Th) clones secrete the latent form of transforming growth factor beta (TGF-beta), in which the mature TGF-beta protein is bound to the latency associated peptide (LAP), and is thereby prevented from binding to the TGF-beta receptor. We previously showed that upon T cell receptor (TCR) stimulation, human Treg clones but not Th clones produce active TGF-beta and bear LAP on their surface. Here, we show that latent TGF-beta, i.e. both LAP and mature TGF-beta, binds to GARP, a transmembrane protein containing leucine rich repeats which is present on the surface of stimulated Treg clones but not on Th clones. Membrane localization of latent TGF-beta mediated by binding to GARP may be necessary for the ability of Treg to activate TGF-beta upon TCR stimulation. However, it is not sufficient as lentiviral mediated expression of GARP in human Th cells induces binding of latent TGF-beta to the cell surface, but does not result in the production of active TGF-beta upon stimulation of these Th cells.