TGF- family members are highly pleiotropic cytokines with diverse regulatory functions. TGF- is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGF-binding protein (LTBP) to produce a large latent form. Latent TGF- 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- to the cell surface. We demonstrate that platelets and activated Tregs co-express latent TGF- and GARP on their membranes. The knockdown of GARP mRNA with siRNA prevented surface latent TGF- expression on activated Tregs and recombinant latent TGF-1 is able to bind directly with GARP. Confocal microscopy and immunoprecipitation strongly support their interactions. The role of TGF- on Tregs appears to have dual functions, both for Treg-mediated suppression and infectious tolerance mechanism.transforming growth factor beta ͉ Tregs ͉ latency-associated peptide
TGF-β is a pluripotent cytokine that is capable of inducing the expression of Foxp3 in naive T lymphocytes. TGF-β-induced cells are phenotypically similar to thymic-derived regulatory T cells in that they are anergic and suppressive. We have examined the cytokine and costimulatory molecule requirements for TGF-β-mediated induction and maintenance of Foxp3 by CD4+Foxp3− cells. IL-2 plays a non-redundant role in TGF-β-induced Foxp3 expression. Other common γ-chain-utilizing cytokines were unable to induce Foxp3 expression in IL-2-deficient T cells. The role of CD28 in the induction of Foxp3 was solely related to its capacity to enhance the endogenous production of IL-2. Foxp3 expression was stable in vitro and in vivo in the absence of IL-2. As TGF-β-induced T regulatory cells can be easily grown in vitro, they may prove useful for the treatment of autoimmune diseases, for the prevention of graft rejection, and graft versus host disease.
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