title: Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells.
abstract: The β-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells, but not natural regulatory T (nTreg) cells. Galectin-9 expression within iTreg cells was driven by the transcription factor Smad3, forming a feed-forward loop, which further promoted Foxp3 expression. Galectin-9 increased iTreg cell stability and function by directly binding to its receptor CD44, which formed a complex with transforming growth factor-β (TGF-β) receptor I (TGF-βRI), and activated Smad3. Galectin-9 signaling was further found to regulate iTreg cell induction by dominantly acting through the CNS1 region of the Foxp3 locus. Our data suggest that exogenous galectin-9, in addition to being an effector molecule for Treg cells, acts synergistically with TGF-β to enforce iTreg cell differentiation and maintenance.
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Chuan
authors: C
authors: Wu
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Theresa
authors: T
authors: Thalhamer
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Rafael F
authors: RF
authors: Franca
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Sheng
authors: S
authors: Xiao
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Chao
authors: C
authors: Wang
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Chie
authors: C
authors: Hotta
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Chen
authors: C
authors: Zhu
authors: Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.
authors: Mitsuomi
authors: M
authors: Hirashima
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Ana C
authors: AC
authors: Anderson
authors: Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: vkuchroo@rics.bwh.harvard.edu.
authors: Vijay K
authors: VK
authors: Kuchroo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D037161:Galectins / Q000235:genetics / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D018960:Hyaluronan Receptors / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology; D011991:Receptors, Virus / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051900:Smad3 Protein / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; D037161:Galectins; D000072597:Hepatitis A Virus Cellular Receptor 2; D018960:Hyaluronan Receptors; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D011991:Receptors, Virus; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C476399:Cd44 protein, mouse; C498833:Foxp3 protein, mouse; C442241:Havcr2 protein, mouse; C497791:Smad3 protein, mouse; C508186:galectin 9, mouse