title: Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells.
abstract: Production of active TGF-β1 is one mechanism by which human regulatory T cells (Tregs) suppress immune responses. This production is regulated by glycoprotein A repetitions predominant (GARP), a transmembrane protein present on stimulated Tregs but not on other T lymphocytes (Th and CTLs). GARP forms disulfide bonds with proTGF-β1, favors its cleavage into latent inactive TGF-β1, induces the secretion and surface presentation of GARP·latent TGF-β1 complexes, and is required for activation of the cytokine in Tregs. We explored whether additional Treg-specific protein(s) associated with GARP·TGF-β1 complexes regulate TGF-β1 production in Tregs. We searched for such proteins by yeast two-hybrid assay, using GARP as a bait to screen a human Treg cDNA library. We identified lysosomal-associated transmembrane protein 4B (LAPTM4B), which interacts with GARP in mammalian cells and is expressed at higher levels in Tregs than in Th cells. LAPTM4B decreases cleavage of proTGF-β1, secretion of soluble latent TGF-β1, and surface presentation of GARP·TGF-β1 complexes by Tregs but does not contribute to TGF-β1 activation. Therefore, LAPTM4B binds to GARP and is a negative regulator of TGF-β1 production in human Tregs. It may play a role in the control of immune responses by decreasing Treg immunosuppression.
authors.affiliation: From the de Duve Institute and WELBIO, Université catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Huygens
authors.affiliation: From the de Duve Institute and WELBIO, Université catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Liénart
authors.affiliation: From the de Duve Institute and WELBIO, Université catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dedobbeleer
authors.affiliation: From the de Duve Institute and WELBIO, Université catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Stockis
authors.affiliation: From the de Duve Institute and WELBIO, Université catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Gauthy
authors.affiliation: From the de Duve Institute and WELBIO, Université catholique de Louvain, 1200 Brussels, Belgium.
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Coulie
authors.affiliation: From the de Duve Institute and WELBIO, Université catholique de Louvain, 1200 Brussels, Belgium sophie.lucas@uclouvain.be.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lucas
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D015513:Oncogene Proteins / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D020798:Two-Hybrid System Techniques
chemical_list: C477083:LAPTM4B protein, human; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D015513:Oncogene Proteins; D053773:Transforming Growth Factor beta1
keywords: T cell biology; TGF-β; glycoprotein A repetition predominant (GARP); immunosuppression; leucine-rich repeat-containing protein 32 (LRRC32); protein-protein interaction; regulatory T cells (Tregs); yeast two-hybrid