Disease relevance of Sell

• The occurrence of skin and pulmonary disease in E/P double-mutant mice but not E/L/P triple-mutant mice suggests that deficiency of L-selectin alters the inflammatory response in E/P mutants [1].
• We previously showed that L-selectin deficiency also attenuates experimental metastasis [2].
• Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice [3].
• The cutaneous reverse Arthus reaction requires intercellular adhesion molecule 1 and L-selectin expression [4].
• Furthermore, the mutant mice showed approximately 75% less lymphocyte homing to the peripheral lymph nodes (PLNs) and significantly less contact hypersensitivity response than wild-type mice, demonstrating that GlcNAc6ST-1 and GlcNAc6ST-2 play a major role in L-selectin ligand biosynthesis in HEVs [5].

High impact information on Sell

• Autoreactive T cells specific to these autoantigens are present in most normal individuals but are kept under control by a number of peripheral tolerance mechanisms, among which CD4(+) CD25(+) CD62L(+) T cell-mediated regulation probably plays a central role [6].
• These results identify Core1-beta 3GlcNAcT and its cognate extended core1 O-glycans as essential participants in the expression of the MECA-79-positive, HEV-specific L-selectin ligands required for lymphocyte homing [7].
• L-selectin mediates lymphocyte homing by facilitating lymphocyte adhesion to addressins expressed in the high endothelial venules (HEV) of secondary lymphoid organs [7].
• These observations demonstrate an essential role for Fuc-TVII in E-, P-, and L-selectin ligand biosynthesis and imply that this locus can control leukocyte trafficking in health and disease [8].
• Moreover, alpha 4 beta 7 mediates L-selectin (CD62L)-independent attachment of blood-borne lymphocytes to lamina propria venules in situ [9].

Chemical compound and disease context of Sell

• Moreover, although selectin blockade by heparin 6 to 18 hours after tumor cell injection was synergistic with P-selectin deficiency in reducing metastasis, there was no further effect in L-selectin-deficient animals [2].
• Intercellular adhesion molecule-1 and L-selectin regulate bleomycin-induced lung fibrosis [10].
• Of note, however, unfractionated heparin reduced L-selectin down-regulation and lymphocytopenia [11].
• The polysaccharide fucoidan inhibits microvascular thrombus formation independently from P- and L-selectin function in vivo [12].
• These results provide a mechanism whereby febrile temperatures during infection or clinical hyperthermia potentially amplify the immune response by stimulating L-selectin and alpha4beta7 integrin-dependent homing of immune effector cells to lymphoid tissues [13].

Biological context of Sell

• Mucins generated platelet aggregation in vitro in hirudinized whole blood, but not in platelet-rich leukocyte-free plasma nor in whole blood from L-selectin-deficient mice [14].
• In addition, Gal/ET caused up-regulation of Mac-1 (CD11b/CD18) and shedding of L-selectin from circulating neutrophils [3].
• Furthermore, restimulation of these memory cells by Ag causes them to down-regulate L-selectin, so that memory-effector cells have the same L-selectin- Pgp-1high phenotype as do primary effector cells [15].
• After initial down-regulation of CD127, the responding CD8+ T cell population down-regulated CD62L and re-expressed CD127 [16].
• These data suggest that this endothelial ligand is an adhesion molecule that accomplishes cell binding by presenting carbohydrate(s) to the lectin domain of L Selectin, and the name GLYCAM 1 (GLY-cosylation-dependent Cell Adhesion Molecule 1) has been proposed [17].

Anatomical context of Sell

• Indeed, AgC10 did not inhibit activation by T cells from CD62L-deficient mice (Sell-/-) [18].
• L-selectin mediates lymphocyte homing by facilitating lymphocyte adhesion to unique carbohydrate ligands, sulfated sialyl Lewis(x), which are expressed on high endothelial venules (HEV) in secondary lymphoid organs [19].
• The expression of the leukocyte EL-246 antigen was regulated in the same manner as L-selectin and EL-246 recognized anti-L-selectin mAb affinity-purified antigen in SDS/PAGE Western blot analysis [20].
• We conclude that leukocyte-expressed PSGL-1 serves as the main L-selectin ligand in inflamed postcapillary venules [21].
• Frame-to-frame video analysis of L-selectin-dependent rolling in wild-type mice showed that the majority of observed L-selectin-dependent leukocyte rolling was between free flowing leukocytes and already adherent leukocytes or possibly leukocyte fragments, followed by E-selectin-dependent leukocyte rolling along the endothelium [21].

Associations of Sell with chemical compounds

• These results suggest that an adhesion cascade, which includes L-selectin/PNAd, alpha4beta1 integrin/VCAM-1, and LFA-1, targets specific lymphocyte subsets to BALT [22].
• P-selectin glycoprotein ligand-1 mediates L-selectin-dependent leukocyte rolling in venules [21].
• The interaction of L-selectin expressed on lymphocytes with sulfated sialomucin ligands such as CD34 and GlyCAM-1 on high endothelial venules (HEV) of lymph nodes results in lymphocyte rolling and is essential for lymphocyte recruitment [23].
• Heparin (an antithrombin-potentiating agent that can also block P- and L-selectin recognition of ligands) ameliorated this platelet aggregation, but had no additional effect in P- or L-selectin-deficient mice [14].
• To investigate the role of E- and L-selectin in this process, C3Heb/FeJ mice were treated with 700 mg/kg galactosamine and 100 microgram/kg endotoxin (Gal/ET) [3].

Physical interactions of Sell

• At concentrations just above its mean serum level (approximately 1.5 microg/ml or approximately 30 nM), GlyCAM-1 binds multivalently to immobilized CD62L [24].
• Initially we used fluorescent microspheres to study the potential of L-selectin and the minimal selectin ligand sialyl Lewis(x) (sLe(x)) to interact with postcapillary venules in the absence of PSGL-1 [25].
• Compounds 1 and 2 were 2 times more potent than the sLe(X) tetrasaccharide toward E-selectin binding and up to 4 times more potent than sLe(X) toward P- and L-selectin binding [26].

Regulatory relationships of Sell

• LSST enhances L-selectin-mediated adhesion under shear compared to nonsulfated controls [19].
• Microspheres coated with combinations of L-selectin and sLe(x) interacted with surgically stimulated cremaster venules in a P-selectin-dependent manner [25].
• It has not been determined whether L-selectin-mediated rolling can promote leukocyte adhesion in vivo independent of P- and E-selectin [27].
• This E-selectin-mediated migration of PSGL-1-deficient or wild-type Th1 cells was not altered by injecting a blocking antibody to L-selectin [28].
• Intravital microscopy experiments revealed that MECA-79-reactive ligands depend primarily on FucT-VII, whereas MECA-79-independent medullary L-selectin ligands are regulated by FucT-IV [29].

Other interactions of Sell

• Rolling did not involve L-selectin, but was partially reduced in wild-type mice treated with antibodies to P- or E-selectin and in mice that were deficient in these two selectins [30].
• CD4(+) CD25(+) CD62L(+) regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice [31].
• Our results demonstrate that HEC-GlcNAc6ST contributes predominantly, but not exclusively, to the sulfation of HEV ligands for L-selectin and that alternative, non-MECA79-reactive ligands are present in the absence of HEC-GlcNAc6ST [23].
• Metastasis was attenuated in mice missing these induced endogenous L-selectin ligands due to fucosyltransferase-7 deficiency [2].
• It follows that soluble GlyCAM-1 may cross-link CD62L when it binds to cells, suggesting a mechanism for signal transduction [24].

Analytical, diagnostic and therapeutic context of Sell

• The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7 [32].
• In CD56bright cells and a subpopulation of CD56dim cells, L-selectin ligation by mAb cross-linking activated lymphocyte function-associated Ag 1 (LFA-1), a second adhesion molecule required for leukocyte extravasation [33].
• L-selectin is involved in lymphocyte migration to sites of inflammation in the skin: delayed rejection of allografts in L-selectin-deficient mice [34].
• Microspheres coated with either L-selectin or sLe(x) alone showed less evidence of interaction [25].
• All three chimeras bound to the natural ligands of L-selectin on specialized high endothelial venules in both human and murine lymphoid organs as determined by immunohistochemistry and were able to precipitate 50- and 90-kDa sulfated ligands from organ cultures of murine peripheral and mesenteric lymph nodes [35].

References