Open AccessGARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3 + regulatory T cells
Author(s) -
Dat Q. Tran,
John Andersson,
Rui Wang,
H. E. Ramsey,
Derya Unutmaz,
Ethan M. Shevach
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0901944106
Subject(s) - microbiology and biotechnology , foxp3 , biology , immunoprecipitation , gene knockdown , transforming growth factor , platelet , regulatory t cell , immunology , t cell , gene , immune system , biochemistry , il 2 receptor , antibody
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.