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Expression of Wiskott-Aldrich Syndrome Protein in Dendritic Cells Regulates Synapse Formation and Activation of Naive CD8⁺ T Cells¹

Julian Pulecio^2,*, Elisa Tagliani^2,*, Alix Scholer, Francesca Prete^*, Luc Fetler, Oscar R. Burrone^* and Federica Benvenuti^3,*

^* International Centre for Genetic Engineering and Biotechnology, Trieste, Italy; Centre National de la Recherche Scientifique UMR 168, Laboratoire Physico-Chimie Curie, Institut Curie, Paris, France; and Institut National de la Santé et de la Recherche Medicale U653, Immunité et Cancer, Pavillon Pasteur, Institut Curie, Paris, France

The Wiskott-Aldrich syndrome protein (WASp) is a key regulator of actin polimerization in hematopoietic cells. Mutations in WASp cause a severe immunodeficiency characterized by defective initiation of primary immune response and autoimmunity. The contribution of altered dendritic cells (DCs) functions to the disease pathogenesis has not been fully elucidated. In this study, we show that conventional DCs develop normally in WASp-deficient mice. However, Ag targeting to lymphoid organ-resident DCs via anti-DEC205 results in impaired naive CD8⁺ T cell activation, especially at low Ag doses. Altered trafficking of Ag-bearing DCs to lymph nodes (LNs) accounts only partially for defective priming because correction of DCs migration does not rescue T cell activation. In vitro and in vivo imaging of DC-T cell interactions in LNs showed that cytoskeletal alterations in WASp null DCs causes a reduction in the ability to form and stabilize conjugates with naive CD8⁺ T lymphocytes both in vitro and in vivo. These data indicate that WASp expression in DCs regulates both the ability to traffic to secondary lymphoid organs and to activate naive T cells in LNs.

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 research was supported by Telethon Grant GGP06267.

² J.P. and E.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Federica Benvenuti, Molecular Immunology, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, Italy. E-mail address: benvenut{at}icgeb.org

⁴ Abbreviations used in this paper: DC, dendritic cell; WASp, Wiskott-Aldrich syndrome protein; LN, lymph nodes; BM, bone marrow derived; WT, wild type; OT-I cells, OVA-specific CD8 T cell; CMTMR, orange fluorescent tetramethylrhodamine cell tracker orange.

⁵ The online version of this article contains supplemental material.