Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells

Production of active TGF-beta 1 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-beta 1, favors its cleavage into latent inactive TGF-beta 1, induces the secretion and surface presentation of GARP.latent TGF-beta 1 complexes, and is required for activation of the cytokine in Tregs. We explored whether additional Treg-specific protein(s) associated with GARP.TGF-beta 1 complexes regulate TGF-beta 1 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-beta 1, secretion of soluble latent TGF-beta 1, and surface presentation of GARP.TGF-beta 1 complexes by Tregs but does not contribute to TGF-beta 1 activation. Therefore, LAPTM4B binds to GARP and is a negative regulator of TGF-beta 1 production in human Tregs. It may play a role in the control of immune responses by decreasing Treg immunosuppression.