Sialoadhesin Ligand Expression Identifies a Subset of CD4+Foxp3− T Cells with a Distinct Activation and Glycosylation Profile

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 Maackia amurensis 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 N-glycan rather than O-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.

Siglec‐1 inhibits RSV‐induced interferon gamma production by adult T cells in contrast to newborn T cells

“…CD43 is a highly sialylated receptor on T cells and has been identified as the major receptor for Siglec‐1 27. T cells from mice lacking CD43 are able to bind Siglec‐1, which suggests that in mice another receptor may also be involved 28. However, in humans only human CD43 has been proposed as the main receptor for Siglec‐1 27.…”

Siglec-mediated regulation of immune cell function in disease

“…Similarly, a subset of T effector cells also upregulates sialoadhesin ligands on activation, leading to T cell apoptosis (see Fig. 1e) 103 . Hence, the upregulation of sialoadhesin ligands on different T cell subsets appears to play a role in sialoadhesin-dependent immunoregulation.…”

Sialoadhesin deficiency does not influence the severity of lupus nephritis in New Zealand Black x New Zealand White F1 mice

“…Recently, we confirmed the abundance of SnL on Tregs and also identified a novel subset of activated CD4 + Foxp3 - Teffs bearing SnL following TCR ligation in vitro [22]. A phenotypically similar subset of SnL + CD4 + Foxp3 - Teffs was identified in proteinuric NZBWF1 mice, with the frequency of this subset correlating closely with disease status (proteinuria presence versus absence) [22]. We therefore hypothesized that Sn deficiency might be associated with an augmented disease severity due to an increase in these highly activated CD4 + Foxp3 - T cells.…”