Mitochondrial inclusions in fibroblast culture from a patient with beta-methylcrotonylglycinuria.

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⁺Foxp3⁺ regulatory T cells (Tregs) and inhibited their proliferation. In this study, we examined the induction of Sn ligands (SnL) on all splenic CD4⁺ T cells following in vitro activation. Most CD4⁺ Tregs strongly upregulated SnL, whereas only a small subset of ∼20% CD4⁺Foxp3⁻ T cells (effector T cells [Teffs]) upregulated SnL. SnL⁺ 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⁻ Teffs. Coculture of activated Teffs with Sn⁺ macrophages or Sn⁺ 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⁺ 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⁺Foxp3⁻ 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⁺ Teffs that are implicated in the pathogenesis of autoimmune diseases.