GARP Is Regulated by miRNAs and Controls Latent TGF-β1 Production by Human Regulatory T Cells

GARP is a transmembrane protein present on stimulated human regulatory T lymphocytes (Tregs), but not on other T lymphocytes (Th cells). It presents the latent form of TGF-beta 1 on the Treg surface. We report here that GARP favors the cleavage of the pro-TGF-beta 1 precursor and increases the amount of secreted latent TGF-beta 1. Stimulated Tregs, which naturally express GARP, and Th cells transfected with GARP secrete a previously unknown form of latent TGF-beta 1 that is disulfide-linked to GARP. These GARP/TGF-beta 1 complexes are possibly shed from the T cell surface. Secretion of GARP/TGF-beta 1 complexes was not observed with transfected 293 cells and may thus be restricted to the T cell lineage. We conclude that in stimulated human Tregs, GARP not only displays latent TGF-beta 1 at the cell surface, but also increases its secretion by forming soluble disulfide-linked complexes. Moreover, we identified six microRNAs (miRNAs) that are expressed at lower levels in Treg than in Th clones and that target a short region of the GARP 3' UTR. In transfected Th cells, the presence of this region decreased GARP levels, cleavage of pro-TGF-beta 1, and secretion of latent TGF-beta 1.