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-β1 on the Treg surface. We report here that GARP favors the cleavage of the pro-TGF-β1 precursor and increases the amount of sec...

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Bibliographic Details
Published in:PloS one 2013-09, Vol.8 (9), p.e76186-e76186
Main Authors: Gauthy, Emilie, Cuende, Julia, Stockis, Julie, Huygens, Caroline, Lethé, Bernard, Collet, Jean-François, Bommer, Guido, Coulie, Pierre G, Lucas, Sophie
Format: Article
Language:English
Subjects:
3' Untranslated regions
Adenosine
Blotting, Western
Cancer
Cell lineage
Cell surface
Cleavage
Cloning
Cytokines
Enzyme-Linked Immunosorbent Assay
HEK293 Cells
Helper cells
Humans
Immunoprecipitation
Immunoregulation
Luciferases
Lymphocytes
Lymphocytes T
Membrane Proteins - immunology
Membrane Proteins - metabolism
MicroRNAs
MicroRNAs - metabolism
miRNA
Peptides
Proteins
Reverse Transcriptase Polymerase Chain Reaction
T cell receptors
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
Transforming Growth Factor beta1 - metabolism
Transforming growth factor-b1
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0076186