title: Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25- T cells in response to inflammation.
abstract: Thymus-derived CD4+ CD25+ T regulatory cells (Tregs) are essential for the maintenance of self-tolerance. What critical factors and conditions are required for the extra-thymic development of Tregs remains an important question. In this study, we show that the anti-inflammatory extracellular matrix protein, thrombospondin-1, promoted the generation of human peripheral regulatory T cells through the ligation of one of its receptor, CD47. CD47 stimulation by mAb or a thrombospondin-1 peptide induced naive or memory CD4+ CD25- T cells to become suppressive. The latter expressed increased amounts of CTLA-4, OX40, GITR, and Foxp3 and inhibited autologous Th0, Th1, and Th2 cells. Their regulatory activity was contact dependent, TGF-beta independent, and partially circumvented by IL-2. This previously unknown mechanism to induce human peripheral Tregs in response to inflammation may participate to the limitation of collateral damage induced by exacerbated responses to self or foreign Ags and thus be relevant for therapeutic intervention in autoimmune diseases and transplantation.
authors.affiliation: Immunoregulation Centre Hospitalier de l'Université de Montreal, Research Center , Hospital Notre-Dame, Montreal, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Grimbert
authors.forename: Salim
authors.initials: S
authors.lastname: Bouguermouh
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Baba
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nakajima
authors.forename: Zoulfia
authors.initials: Z
authors.lastname: Allakhverdi
authors.forename: Deborah
authors.initials: D
authors.lastname: Braun
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.forename: Manuel
authors.initials: M
authors.lastname: Rubio
authors.forename: Guy
authors.initials: G
authors.lastname: Delespesse
authors.forename: Marika
authors.initials: M
authors.lastname: Sarfati
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D051928:CD47 Antigen / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D007156:Immunologic Memory; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology*; D019700:Thrombospondin 1 / Q000378:metabolism / Q000502:physiology*
chemical_list: D051928:CD47 Antigen; C497894:CD47 protein, human; D018836:Inflammation Mediators; D008024:Ligands; D015375:Receptors, Interleukin-2; D019700:Thrombospondin 1