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

de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
European Journal of Immunology (Impact Factor: 4.52). 12/2009; 39(12):3315-22. DOI: 10.1002/eji.200939684
Source: PubMed

ABSTRACT Human Treg and Th clones secrete the latent form of 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 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 glycoprotein A repetitions predominant (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.

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Available from: Sophie Lucas, Jul 15, 2015
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    • "Although repeatedly observed in disease models (Nakamura et al., 2001) a direct contribution of TGF-β in Treg suppression remained controversial because anti-TGF-β antibodies and soluble TGF-RII failed to affect the suppressive function of Treg (Andersson et al., 2008). Recently, " glycoprotein A repetitions predominant " (GARP) expressed on the surface of Treg upon activation (Wang et al., 2008, 2009; D'Alise et al., 2011) has been shown to act as a receptor for the TGF-β/LAP complex (Stockis et al., 2009). Reminiscent of infectious Treg suppression (Jonuleit et al., 2002; Stassen et al., 2004) latent TGF-β bound to GARP on the surface of activated Treg has been demonstrated to convert responder T cells into induced Treg (Andersson et al., 2008). "
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    • "Based on the knowledge that malaria parasites can activate the soluble form of latent TGFb (Omer et al., 2003), and upon evidence of such property in the PfSEs used in these studies (see Fig. S3), we explored whether or not the effects of PfSEs could be related to the activation of membrane-bound TGFb. Since the low amounts of active TGFb bound to membrane of Treg cells make its detection difficult through conventional techniques, we decided to study the phosphorylation of SMAD 2/3 proteins as an indirect measure of active TGFb generation, and consequent TGFbR activation (Kang et al., 2009; Stockis et al., 2009a). CD4 + cells from five different donors were activated with aCD3/CD28-coupled beads for 5 days and total CD25 + and CD25 -cells were isolated from activated cultures through magnetic sorting with aCD25 antibodies coupled beads. "
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