Abstract

Sialoadhesin (Sn) is a sialic acid–binding Ig-like lectin expressed selectively on macrophage subsets. In a model of experimental autoimmune encephalomyelitis, Sn interacted with sialylated ligands expressed selectively on CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (Tregs) and inhibited their proliferation. In this study, we examined the induction of Sn ligands (SnL) on all splenic CD4<sup>+</sup> T cells following in vitro activation. Most CD4<sup>+</sup> Tregs strongly upregulated SnL, whereas only a small subset of ∼20% CD4<sup>+</sup>Foxp3<sup>−</sup> T cells (effector T cells [Teffs]) upregulated SnL. SnL<sup>+</sup> Teffs displayed higher levels of activation markers CD25 and CD69, exhibited increased proliferation, and produced higher amounts of IL-2 and IFN-γ than corresponding SnL<sup>−</sup> Teffs. Coculture of activated Teffs with Sn<sup>+</sup> macrophages or Sn<sup>+</sup> Chinese hamster ovary cells resulted in increased cell death, suggesting a regulatory role for Sn–SnL interactions. The key importance of α2,3-sialylation in SnL expression was demonstrated by increased binding of α2,3-linkage–specific <i>Maackia amurensis</i> lectin, increased expression of α2,3-sialyltransferase ST3GalVI, and loss of SnL following treatment with an α2,3-linkage–specific sialidase. The induction of SnL on activated CD4<sup>+</sup> T cells was dependent on <i>N</i>-glycan rather than <i>O</i>-glycan biosynthesis and independent of the mucin-like molecules CD43 and P-selectin glycoprotein ligand-1, previously implicated in Sn interactions. Induction of ligands on CD4<sup>+</sup>Foxp3<sup>−</sup> Teffs was also observed in vivo using the New Zealand Black × New Zealand White F1 murine model of spontaneous lupus and SnL levels on Teffs correlated strongly with the degree of proteinuria. Collectively, these data indicate that SnL is a novel marker of activated CD4<sup>+</sup> Teffs that are implicated in the pathogenesis of autoimmune diseases.

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