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.
Highlights
TGF-1 produced by regulatory T lymphocytes suppresses excessive immune responses
Identification of glycoprotein A repetitions predominant (GARP) Binding Proteins in a Yeast Two-hybrid System—To identify proteins binding to GARP in human Tregs, we used the yeast two-hybrid system known as splitubiquitin
The two other members of the family are LAPTM4A and LAPTM5, with 46 and 23% sequence identities with LAPTM4B, respectively
Summary
TGF-1 produced by regulatory T lymphocytes suppresses excessive immune responses. Results: Lysosomal-associated transmembrane protein 4B (LAPTM4B) was found to inhibit TGF-1 production in Tregs. Production of active TGF-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). As a source of human Tregs, we used Treg clones described previously, i.e. pure populations of cells with a demethylated FOXP3i1 allele, or blood CD4ϩCD25ϩCD127lo cells shortly expanded in vitro, i.e. polyclonal populations enriched in cells with a demethylated FOXP3i1 allele Both cell populations are suppressive in vitro, express FOXP3, and, upon TCR stimulation, induce GARP expression and produce active TGF-1 [8, 11, 15, 22,23,24]. On the basis of their suppressive activity and mRNA, protein, and epigenetic profile, we termed these human cells “Tregs” (Treg clones or polyclonal Tregs), as proposed by Abbas et al [25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
