GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells
- PMID: 19651619
- PMCID: PMC2726354
- DOI: 10.1073/pnas.0901944106
GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells
Abstract
TGF-beta family members are highly pleiotropic cytokines with diverse regulatory functions. TGF-beta is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGFbeta-binding protein (LTBP) to produce a large latent form. Latent TGF-beta 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-beta to the cell surface. We demonstrate that platelets and activated Tregs co-express latent TGF-beta and GARP on their membranes. The knockdown of GARP mRNA with siRNA prevented surface latent TGF-beta expression on activated Tregs and recombinant latent TGF-beta1 is able to bind directly with GARP. Confocal microscopy and immunoprecipitation strongly support their interactions. The role of TGF-beta on Tregs appears to have dual functions, both for Treg-mediated suppression and infectious tolerance mechanism.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
![Fig. 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2726354/bin/zpq9990987620001.gif)
![Fig. 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2726354/bin/zpq9990987620002.gif)
![Fig. 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2726354/bin/zpq9990987620003.gif)
![Fig. 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2726354/bin/zpq9990987620004.gif)
![Fig. 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2726354/bin/zpq9990987620005.gif)
Similar articles
-
Regulation of the expression of GARP/latent TGF-β1 complexes on mouse T cells and their role in regulatory T cell and Th17 differentiation.J Immunol. 2013 Jun 1;190(11):5506-15. doi: 10.4049/jimmunol.1300199. Epub 2013 May 3. J Immunol. 2013. PMID: 23645881 Free PMC article.
-
GARP-TGF-β complexes negatively regulate regulatory T cell development and maintenance of peripheral CD4+ T cells in vivo.J Immunol. 2013 May 15;190(10):5057-64. doi: 10.4049/jimmunol.1300065. Epub 2013 Apr 10. J Immunol. 2013. PMID: 23576681 Free PMC article.
-
The Tregs' world according to GARP.Eur J Immunol. 2009 Dec;39(12):3296-300. doi: 10.1002/eji.200940117. Eur J Immunol. 2009. PMID: 19904770
-
Garp as a therapeutic target for modulation of T regulatory cell function.Expert Opin Ther Targets. 2017 Feb;21(2):191-200. doi: 10.1080/14728222.2017.1275568. Epub 2016 Dec 29. Expert Opin Ther Targets. 2017. PMID: 28001437 Review.
-
GARP: a surface molecule of regulatory T cells that is involved in the regulatory function and TGF-β releasing.Oncotarget. 2016 Jul 5;7(27):42826-42836. doi: 10.18632/oncotarget.8753. Oncotarget. 2016. PMID: 27095576 Free PMC article. Review.
Cited by
-
Distinct Localization, Transcriptional Profiles, and Functionality in Early Life Tonsil Regulatory T Cells.J Immunol. 2024 Aug 1;213(3):306-316. doi: 10.4049/jimmunol.2300890. J Immunol. 2024. PMID: 38905110
-
Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective.Pharmaceuticals (Basel). 2024 Apr 20;17(4):533. doi: 10.3390/ph17040533. Pharmaceuticals (Basel). 2024. PMID: 38675493 Free PMC article. Review.
-
Pathways and molecules for overcoming immunotolerance in metastatic gastrointestinal tumors.Front Immunol. 2024 Apr 5;15:1359914. doi: 10.3389/fimmu.2024.1359914. eCollection 2024. Front Immunol. 2024. PMID: 38646539 Free PMC article. Review.
-
TGF-β signaling in health, disease, and therapeutics.Signal Transduct Target Ther. 2024 Mar 22;9(1):61. doi: 10.1038/s41392-024-01764-w. Signal Transduct Target Ther. 2024. PMID: 38514615 Free PMC article. Review.
-
Regulatory T Cells for Control of Autoimmunity.Adv Exp Med Biol. 2024;1444:67-82. doi: 10.1007/978-981-99-9781-7_5. Adv Exp Med Biol. 2024. PMID: 38467973
References
-
- Gleizes PE, et al. TGF-beta latency: Biological significance and mechanisms of activation. Stem Cells. 1997;15:190–197. - PubMed
-
- Lawrence DA. Latent-TGF-beta: An overview. Mol Cell Biochem. 2001;219:163–170. - PubMed
-
- Grainger DJ, Wakefield L, Bethell HW, Farndale RW, Metcalfe JC. Release and activation of platelet latent TGF-beta in blood clots during dissolution with plasmin. Nat Med. 1995;1:932–937. - PubMed
-
- Gandhi R, Anderson DE, Weiner HL. Cutting edge: Immature human dendritic cells express latency-associated peptide and inhibit T cell activation in a TGF-beta-dependent manner. J Immunol. 2007;178:4017–4021. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous