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,
* Immunoregulation and
Allergy Laboratories, Centre Hospitalier de l’Université de Montreal, Research Center, Hospital Notre-Dame, Montreal, Quebec, Canada;
Laboratory for Allergy Transcriptome, Institute for Physical and Chemical Research, Research Center for Allergy and Immunology, Tokyo, Japan.; and
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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-
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Canadian Institute for Health and Research (MOP-4490). Philippe Grimbert was sponsored by the French Society of Transplantation.
2 P.G. and S.B. contributed equally to this work.
3 Current address: Institut Pasteur, 25–28 rue du Dr Roux, 75724 Paris Cedex 15, France.
4 Address correspondence and reprint requests to Dr. Marika Sarfati, Immunoregulation Laboratory, Centre Hospitalier de l’Université de Montreal, Hopital Notre-Dame (Pavillon Mailloux, M4211K), 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada. E-mail address: m.sarfati{at}umontreal.ca
5 Abbreviations used in this paper: Treg, regulatory T cell; TSP, thrombospondin-1; CBMC, cord blood mononuclear cell; DC, dendritic cell.
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