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* Institute for Physiological Chemistry and Pathobiochemistry, Muenster University, Muenster, Germany;
Vessel Wall Biology, Institute for Experimental Medical Sciences, Lund University, Lund, Sweden;
Department of Dermatology and Interdisciplinary Center of Clinical Research, University of Muenster, Muenster, Germany; and
The Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, United Kingdom
An important regulatory suppressive function in autoimmune and other inflammatory processes has been ascribed to CD4+Foxp3+ regulatory T cells (Tregs), which requires direct cell-cell communication between Tregs, effector T cells, and APCs. However, the molecular basis for these interactions has not yet been clarified. We show here that sialoadhesin (Sn), the prototype of the siglec family of sialic acid-binding transmembrane proteins, expressed by resident and activated tissue-infiltrating macrophages, directly binds to Tregs, negatively regulating their expansion in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). In this model, macrophages infiltrate the CNS exhibiting tissue-destructing and demyelinating activity, leading to MS-like symptoms. We show here that severity of EAE symptoms is reduced in Sn knockout (KO) mice compared with wild-type littermates due to an up-regulation of CD4+Foxp3+ Treg lymphocytes. Through the use of a Sn fusion protein, Tregs were shown to express substantial amounts of Sn ligand on their cell surface, and direct interaction of Sn+ macrophages with Tregs specifically inhibited Treg but not effector T lymphocyte proliferation. Conversely, blocking of Sn on macrophages by Sn-specific Abs resulted in elevated proliferation of Tregs. Data indicate that Sn+ macrophages regulate Treg homeostasis which subsequently influences EAE progression. We propose a new direct cell-cell interaction-based mechanism regulating the expansion of the Tregs during the immune response, representing a "dialogue" between Sn+ macrophages and Sn-accessible sialic acid residues on Treg lymphocytes.
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 German (SFB293 A14) and Swedish Research Councils (621-2001-2142 and K2004-33X-15076-01A), the Alfred Österlund stiftelse, Greta och Johan Kocks stiftelse, Crafoordaska stiftelsen, Kungliga fysiografiska sällskapet i Lund, the Interdisciplinary Clinical Research Center (Lo2/017/07) Muenster, Germany, and Wellcome Trust Senior Research Fellowship WT081882MA (to P.R.C.).
2 Address correspondence and reprint requests to Dr. Lydia M. Sorokin, Institute for Physiological Chemistry and Pathobiochemistry, Muenster University, Waldeyerstrasse 15, 48149 Muenster, Germany, E-mail address: sorokin{at}uni-muenster.de
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; Sn, sialoadhesin; MOG, myelin oligodendrocyte glycoprotein; Treg, regulatory T cell; Teff, effector T cell; EAU, experimental autoimmune uveoretinitis; KO, knockout; LN, lymph node; DC, dendritic cell.
4 The online version of this article contains supplemental material.
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