Sialoadhesin-positive macrophages bind regulatory T cells, negatively controlling their expansion and autoimmune disease progression

Chuan Wu, Uwe Rauch, Eva Korpos, Jian Song, Karin Loser, Paul R. Crocker, Lydia M. Sorokin

    Research output: Contribution to journalArticlepeer-review

    57 Citations (Scopus)

    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 languageEnglish
    Pages (from-to)6508-6516
    Number of pages9
    JournalJournal of Immunology
    Volume182
    Issue number10
    DOIs
    Publication statusPublished - 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

    Cite this