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: 4.03). 12/2009; 39(12):3315-22. DOI: 10.1002/eji.200939684
Source: PubMed


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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    • "Glycoprotein A repetitions predominant (GARP), an 80-kDa type I transmembrane glycoprotein leucine rich repeat (LRR), is highly expressed in activated Tregs [19]–[21]. GARP binds directly to LAP and tethers latent TGF­β on the surface of activated Tregs, and it has been clarified that GARP is a receptor for latent TGF­β [22]–[23]. "
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    ABSTRACT: CD4(+) latency-associated peptide (LAP)(+) regulatory T cells (Tregs) are a newly discovered T cell subset in humans and the role of these cells in patients with acute coronary syndrome (ACS) has not been explored. We designed to investigate whether circulating frequency and function of CD4(+)LAP(+) Tregs are defective in ACS. One hundred eleven ACS patients (acute myocardial infarction and unstable angina) and 117 control patients were enrolled in the study. The control patients consisted of chronic stable angina (CSA) and chest pain syndrome (CPS). The frequencies of circulating CD4(+)LAP(+) Tregs and the expression of the transmembrane protein glycoprotein-A repetitions predominant (GARP) on CD4(+) T cells were determined by flow cytometry. The function of CD4(+)LAP(+) Tregs was detected using thymidine uptake. Serum interleukin-10 (IL-10) and transforming growth factor-β protein (TGF-β) levels were detected using ELISA and expression of GARP mRNA in peripheral blood mononuclear cells (PBMCs) was measured by real time-polymerase chain reaction. We found ACS patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs, and the function of these cells was reduced compared to controls. The expression of GARP in CD4(+) T cells and the serum levels of TGF-β in ACS patients were lower than those of control patients. The serum levels of IL-10 were similar between the two cohorts. A novel regulatory T cell subset, defined as CD4(+)LAP(+) T cells is defective in ACS patients.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "We also reported that anti-TGFβ receptor II (TGFβRII) treatment of ConA-stimulated Th cells abrogated the Th to Treg conversion, supporting a role for TGFβ/TGFβRII signaling in this conversion process [17]. Recent studies indicate that peripheral Treg cells, once activated, express both mTGFβ and GARP on their surface and that both molecules are instrumental in Treg cell suppressor function [11,12]. It is not known if this TGFβ/GARP complex plays a role in recruitment of Treg cells from the Th cell pool but evidence suggests that it may be integral to contact-dependent TGFβ signaling through TGFβRII [11,12]. "
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    ABSTRACT: We and others have previously reported that cell membrane-bound TGFbeta (mTGFbeta) on activated T regulatory (Treg) cells mediates suppressor function. Current findings suggest that a novel protein known as Glycoprotein A Repetitions Predominant (GARP) anchors mTGFbeta to the Treg cell surface and facilitates suppressor activity. Recently, we have described that GARP+TGFbeta+ Treg cells expand during the course of FIV infection. Because Treg cells are anergic and generally exhibit poor proliferative ability, we asked how Treg homeostasis is maintained during the course of feline immunodeficiency virus (FIV) infection. Here, we report that Treg cells from FIV+ cats express GARP and mTGFbeta and convert T helper (Th) cells into phenotypic and functional Treg cells. Th to Treg conversion was abrogated by anti-TGFbeta or anti-GARP treatment of Treg cells or by anti-TGFbetaRII treatment of Th cells, suggesting that Treg cell recruitment from the Th pool is mediated by TGFbeta/TGFbetaRII signaling and that cell-surface GARP plays a major role in this process. These findings suggest Th to Treg conversion may initiate a cascade of events that contributes to the maintenance of virus reservoirs, progressive Th cell immunosuppression, and the development of immunodeficiency, all of which are central to the pathogenesis of AIDS lentivirus infections.
    Full-text · Article · Jan 2014 · Virology Journal
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    • "After TCR stimulation, Tregs bear latent TGF-β1 on their surface [18,19]. This occurs through binding to GARP [17,20], a transmembrane protein with a large extracellular domain containing 20 leucine-rich repeats. GARP protein was found after TCR stimulation in human Tregs, but not in other T lymphocytes [17,20–22], explaining why only Tregs display latent TGF-β1 on their surface. "
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    ABSTRACT: 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-β1 on the Treg surface. We report here that GARP favors the cleavage of the pro-TGF-β1 precursor and increases the amount of secreted latent TGF-β1. Stimulated Tregs, which naturally express GARP, and Th cells transfected with GARP secrete a previously unknown form of latent TGF-β1 that is disulfide-linked to GARP. These GARP/TGF-β1 complexes are possibly shed from the T cell surface. Secretion of GARP/TGF-β1 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-β1 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-β1, and secretion of latent TGF-β1.
    Full-text · Article · Sep 2013 · PLoS ONE
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