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Functional Role of P-Selectin Glycoprotein Ligand 1/P-Selectin Interaction in the Generation of Tolerogenic Dendritic Cells¹

Ana Urzainqui^*, Gloria Martínez del Hoyo^*, Amalia Lamana^*, Hortensia de la Fuente^*, Olga Barreiro^*, Isabel M. Olazabal^*, Pilar Martin, Martin K. Wild, Dietmar Vestweber, Roberto González-Amaro and Francisco Sánchez-Madrid^2,*,

^* Servicio de Inmunología, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, and Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain; Max Planck Institute for Molecular Biomedicine, Münster, Germany; and Departamento de Inmunología, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México

Dendritic cells (DCs) have a key role in both the generation of the immune response and the induction of tolerance to self-Ags. In this work, the possible role of P-selectin glycoprotein ligand 1 (PSGL-1) on the tolerogenic activity of human DCs was explored. We found that the engagement of PSGL-1 by P-selectin on DCs induced the expression of c-Fos, IDO, IL-10, and TGF-β genes. Remarkably, stimulation of DCs through PSGL-1 with P-selectin enhanced their capability to generate CD4⁺CD25⁺Foxp3⁺ regulatory T cells, which expressed high levels of TGF-β1 mRNA, synthesized IL-10, and suppressed the proliferation of autologous CD4⁺CD25^– T cells. Accordingly, we found that DCs from PSGL-1^–/– mice expressed higher levels of MHC class II molecules, and exhibited an enhanced immunogenicity compared with wild-type mice. In addition, the percentage of CD4⁺CD25⁺Foxp3⁺ regulatory T cells in the thymus of PSGL-1-deficient animals was significantly reduced. Our data reveal an unexpected role of PSGL-1 on the tolerogenic function of DCs, and the regulation of the immune response.

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 Grant BFU2005-08435/BMC from The Spanish Ministry of Education and Science, The Ayuda a la Investigación Básica 2002 from Juan March Foundation, Grant LSHG-CT-2003-502935 from European Network MAIN (to F.S.-M.), Grant SFB293 from the Deutsche Forschungsgemeinschaft (to M.K.W.), by the Max-Planck-Gesellschaft (to D.V.), and by Grant 05/00127 from Fondo de Investigaciones Sanitarias (to A.U.).

² Address correspondence and reprint requests Dr. Francisco Sánchez-Madrid, Servicio de Inmunología, Hospital Universitario de La Princesa, Diego de León 62, 28006 Madrid, Spain. E-mail address: fsanchez.hlpr{at}salud.madrid.org

³ Abbreviations used in this paper: DC, dendritic cell; Treg, regulatory T; PSGL-1, P-selectin glycoprotein ligand 1; LC, Langerhans-like DC; mDC, monocyte-derived DC; pDC, plasmacytoid DC; cDC, conventional DC; Flt3L, Flt3 ligand.