Role of GARP in the activation of latent TGF-ß1.

TGF-ß1, 2 and 3 cytokines are involved in many cellular processes including cell proliferation, differentiation, migration and survival. Whereas TGF-ß2 and 3 play important roles in embryonic development, TGF-ß1 is mostly implicated in controlling immune responses after birth. The production of TGF-ß1 is a tightly regulated process, occurring mostly at a post-translational level. Virtually all cells produce the latent, inactive form of TGF-ß1. In latent TGF-ß1, the mature TGF-ß1 dimer is non-covalently associated to the Latency Associated Peptide, or LAP, which prevents binding to the TGF-ß1 receptor. Activation of the cytokine implies release of mature TGF-ß1 from LAP. Only a few cell types activate latent TGF-ß1, via mechanisms that are cell type specific. Proteins such as integrins, proteases and thrombospondin-1 activate TGF-ß1 in epithelial cells, fibroblasts and dendritic cells. More recently, the protein GARP was shown to be involved in TGF-ß1 activation by regulatory T cells (Treg), a subset of CD4+ T lymphocytes specialized in suppression of immune responses. GARP is a transmembrane protein that binds latent-TGF-ß1 and tethers it on the Treg surface. The role of GARP was studied mostly in Tregs, and this was recently reviewed in L. Sun, H. Jin and H. Li, Oncotarget, 2016, 7, 42826-42836. However, GARP is also expressed in non-immune cells. This review focuses on the roles of GARP in latent TGF-ß1 activation by immune and non-immune cells.