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

DQ Tran, J Andersson, R Wang… - Proceedings of the …, 2009 - National Acad Sciences
DQ Tran, J Andersson, R Wang, H Ramsey, D Unutmaz, EM Shevach
Proceedings of the National Academy of Sciences, 2009National Acad Sciences
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 …
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.
National Acad Sciences