Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm

TA Springer - Cell, 1994 - Elsevier
Cell, 1994Elsevier
Multiple protein families, each with a distinct function, provide the traffic signals for
leukocytes. The selectin family of adhesion molecules (Figure 2) has an N-terminal domain
homologous to Ca*+-dependent lectins (Rosen, 1993; Bevilacqua, 1993). L-selectin is
expressed on all circulating leukocytes, except for a subpopulation of memory lymphocytes.
P-selectin is stored preformed in the Weibel-Palade bodies of endothelial cells and the a
granules of platelets. In response to mediators of acute inflammation, such as thrombin or …
Multiple protein families, each with a distinct function, provide the traffic signals for leukocytes. The selectin family of adhesion molecules (Figure 2) has an N-terminal domain homologous to Ca*+-dependent lectins (Rosen, 1993; Bevilacqua, 1993). L-selectin is expressed on all circulating leukocytes, except for a subpopulation of memory lymphocytes. P-selectin is stored preformed in the Weibel-Palade bodies of endothelial cells and the a granules of platelets. In response to mediators of acute inflammation, such as thrombin or histamine, P-selectin is rapidly mobilized to the plasma membrane to bind neutrophils and monocytes. E-selectin is induced on vascular endothelial cells by cytokines such as interleukin-1 (IL-l), lipopolysaccharide, or tumor necrosis factor (TNF) and requires de novo mRNA and protein synthesis. Selectins mediate a function unique to the vasculature, the attachment or tethering of flowing leukocytes to the vessel wall through labile adhesions that permit leukocytes to roll in the direction of flow (Lawrence and Springer, 1991; Ley et al., 1991; von Andrian et al., 1991; Mayadas et al., 1993). Selectins can mediate tethering of a flowing cell in the span of a millisecond and, subsequently, rolling. It has been hypothesized that selectins have rapid association (k,.) and dissociation (k,“) rate constants (Lawrence and Springer, 1991), as has recently been confirmed (R. Alon and TAS, unpublished data; Ushiyama et al., 1993).
Carbohydrates and Mucin-like Molecules All selectins appear to recognize a sialylated carbohydrate determinant on their counterreceptors (Lasky, 1992; Rosen, 1993). E-selectin and P-selectin recognize carbohydrate structures that are distinct, but are closely related to the tetrasaccharide sialyl Lewis” and its isomer sialyl Lewisa (Figure 2). The carbohydrate ligand for L-selectin is related to sialyl Lewisa and Lewis” and contains sialic acid and sulfate (Rosen, 1993). The carbohydrate ligands for L-and P-selectin are O-linked to specific mucin-like molecules. Mucins are serine-and threonine-rich proteins that are heavily O-glycosylated and have an extended structure. L-selectin recognizes two mucins in high endothelial venules (HEVs)(Figure 3), glycosylation-dependent cell adhesion molecule 1 (GlyCAM-l), which issecreted (Lasky, 1992; Rosen, 1993), and CD34, which is on the cell surface (Baumhueter et al., 1993). The mucin-like P-selectin glycoprotein ligand (PSGL-1) is a disulfide-linked dimer of 120 kd subunits (Figure 3)(Moore et al., 1992; Sako et al., 1993). PSGL-1 was isolated by screening for cDNA that expressed ligand activity; COS cells must be transfected both with the PSGL-1 cDNA and aB/Cfucosyl transferase cDNA to express P-selectin ligand activity. By contrast, COS cells cotransfected with a cDNA for a91Cfucosyl transferase and another mucin-like molecule expressed by neutrophils, CD43, lack P-selectin ligand activity. Chemoattractants
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