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Abstract
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 Sri 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 Journal of Immunology, 2009, 182: 6508-6516.
Original language | English |
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Pages (from-to) | 6508-6516 |
Number of pages | 9 |
Journal | Journal of Immunology |
Volume | 182 |
Issue number | 10 |
DOIs | |
Publication status | Published - 15 May 2009 |
Keywords
- Central nervous system
- Immunological self-tolerance
- Vivo antigen presentation
- Blood-brain-barrier
- Dendritic cells
- Leukocyte extravasation
- Peripheral homeostasis
- Multiple sclerosis
- Counter-receptor
- Mice
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- 1 Finished
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Aref#d: 19149. Role of Siglecs in Disease (Senior Research Fellowship)
Crocker, P. (Investigator)
1/11/07 → 30/04/13
Project: Research