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GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3 + regulatory T cells

2009; National Academy of Sciences; Volume: 106; Issue: 32 Linguagem: Inglês

10.1073/pnas.0901944106

1091-6490

Dat Q. Tran, John Andersson, Rui Wang, H. E. Ramsey, Derya Unutmaz, Ethan M. Shevach,

Cell Adhesion Molecules Research

TGF-β family members are highly pleiotropic cytokines with diverse regulatory functions. TGF-β is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGFβ-binding protein (LTBP) to produce a large latent form. Latent TGF-β is also found on the surface of activated FOXP3 + regulatory T cells (Tregs), but it is unclear how it is anchored to the cell membrane. We show that GARP or LRRC32, a leucine-rich repeat molecule of unknown function, is critical for tethering TGF-β to the cell surface. We demonstrate that platelets and activated Tregs co-express latent TGF-β and GARP on their membranes. The knockdown of GARP mRNA with siRNA prevented surface latent TGF-β expression on activated Tregs and recombinant latent TGF-β1 is able to bind directly with GARP. Confocal microscopy and immunoprecipitation strongly support their interactions. The role of TGF-β on Tregs appears to have dual functions, both for Treg-mediated suppression and infectious tolerance mechanism.