PSGL‐1 function in immunity and steady state homeostasis

Abstract

The substantial importance of P-selectin glycoprotein ligand 1 (PSGL-1) in leukocyte trafficking has continued to emerge beyond its initial identification as a selectin ligand. PSGL-1 seemed to be a relatively simple molecule with an extracellular mucin domain extended as a flexible rod, teleologically consistent with its primary role in tethering leukocytes to endothelial selectins. The rolling interaction between leukocyte and endothelium mediated by this selectin-PSGL-1 interaction requires branched O-glycan extensions on specific PSGL-1 amino acid residues. In some cells, such as neutrophils, the glycosyltransferases involved in formation of the O-glycans are constitutively expressed, while in other cells, such as T cells, they are expressed only after appropriate activation. Thus, PSGL-1 supports leukocyte recruitment in both innate and adaptive arms of the immune response. A complex array of amino acids within the selectins engage multiple sugar residues of the branched O-glycans on PSGL-1 and provide the molecular interactions responsible for the velcro-like catch bonds that support leukocyte rolling. Such binding of PSGL-1 can also induce signaling events that influence cell phenotype and function. Scrutiny of PSGL-1 has revealed a better understanding of how it performs as a selectin ligand and yielded unexpected insights that extend its scope from supporting leukocyte rolling in inflammatory settings to homeostasis including stem cell homing to the thymus and mature T-cell homing to secondary lymphoid organs. PSGL-1 has been found to bind homeostatic chemokines CCL19 and CCL21 and to support the chemotactic response to these chemokines. Surprisingly, the O-glycan modifications of PSGL-1 that support rolling mediated by selectins in inflammatory conditions interfere with PSGL-1 binding to homeostatic chemokines and thereby limit responsiveness to the chemotactic cues used in steady state T-cell traffic. The multi-level influence of PSGL-1 on cell traffic in both inflammatory and steady state settings is therefore substantially determined by the orchestrated addition of O-glycans. However, central as specific O-glycosylation is to PSGL-1 function, in vivo regulation of PSGL-1 glycosylation in T cells remains poorly understood. It is our purpose herein to review what is known, and not known, of PSGL-1 glycosylation and to update understanding of PSGL-1 functional scope.

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

“…5B). Moreover, two other key glycosyltransferases, b1,4GalT and FucT7, which were shown previously to be involved in the biosynthesis of sLe x motifs on activated T cells (27), were also found to be upregulated on SnL + Teffs (Fig. 5B).…”

“…As CD43 and PSGL-1 are major carriers of O-glycans on T cells (26,27), the failure to see reduced Sn-Fc binding to T cells lacking these glycoproteins suggested that O-glycans were not required for SnL expression. We investigated the nature of carbohydrate structures involved in Sn binding further using inhibitors of N-and Oglycan biosynthesis.…”

“…Previously, CD43 and PSGL-1 were identified as putative counterreceptors for Sn using Sn-Fc pulldown methods with the TK1 T lymphoma cell line (28). These mucin-like glycoproteins contain multiple O-linked glycans terminating in a2,3-linked Sias (26,27,29). However, our analysis of SnL induction on splenocytes from mice deficient in either CD43 or PSGL-1 showed that Sn-Fc binding to activated CD4 + T cells was independent of either of these cell surface mucins (Fig.…”

IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking

“…Specifically, core 2 O-glycans decorated with the tetrasaccharide sialyl Lewis X are critical for mediating the calcium-dependent interaction between selectins and their corresponding ligands (27,28). Furthermore, a variety of molecules can serve as functional P-and E-selectin ligands, including P-selectin glycoprotein ligand-1 (PSGL-1), E-selectin ligand-1 (ESL-1), CD44, and perhaps more yet unidentified glycoproteins (29)(30)(31). Thus, the generation of functional ligands for P-and/or E-selectin on CD8 + T cells likely requires both the expression and appropriate glycosylation of a number of different cell surface proteins.…”

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

“…human scavenger receptor class B, member 2 (SCARB2), also known as lysosomal integral membrane protein 2 (LIMP-2) or CD36b like-2; and P-selectin glycoprotein ligand-1 (PSGL-1), also known as CD162 [9][10][11]. SCARB2 is expressed in most cell types, whereas PSGL-1 is limited to blood cells and endothelial cells, suggesting a distinct role for these two receptors in the pathogenesis of EV71 infection in vivo [12]. An important physiological function of SCARB2 is to transport acid b-glucosidase 1 (GBA1; also known as b-glucocerebrosidase), thereby supporting glycolipid metabolism [13].…”