Neutrophils, Monocytes, and Dendritic Cells Express the Same Specialized Form of PSGL-1 as Do Skin-Homing Memory T Cells: Cutaneous Lymphocyte Antigen

Kieffer, J. David; Fuhlbrigge, Robert C.; Armerding, Dieter; Robert, Caroline; Ferenczi, Katalin; Camphausen, Raymond T.; Kupper, Thomas S.

doi:10.1006/bbrc.2001.5230

Cited by 49 publications

(44 citation statements)

References 48 publications

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“…Induced expression of FUT7 is then stabilized by progressive demethylation of selected additional regulatory elements (including the minimal promoter region), as observed in TEM showing partial demethylation corresponding to the known subfraction of TEM-expressing FUT7. Ex vivo monocytes showed the most widespread demethylation within the FUT7 gene correlating to a constitutive expression of CLA (53). Interestingly, monocytes seem to start transcription further upstream, suggesting that the CNS, which acts as an enhancer in T cells, may drive expression of a monocyte-specific transcript, possibly even independently of the minimal promoter.…”

Section: Discussionmentioning

confidence: 99%

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Pink

Ratsch

Mardahl

et al. 2016

The Journal of Immunology

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E- and P-selectin ligands (E- and P-ligs) guide effector memory T cells into skin and inflamed regions, mediate the inflammatory recruitment of leukocytes, and contribute to the localization of hematopoietic precursor cells. A better understanding of their molecular regulation is therefore of significant interest with regard to therapeutic approaches targeting these pathways. In this study, we examined the transcriptional regulation of fucosyltransferase 7 (FUT7), an enzyme crucial for generation of the glycosylated E- and P-ligs. We found that high expression of the coding gene fut7 in murine CD4+ T cells correlates with DNA demethylation within a minimal promoter in skin/inflammation-seeking effector memory T cells. Retinoic acid, a known inducer of the gut-homing phenotype, abrogated the activation-induced demethylation of this region, which contains a cAMP responsive element. Methylation of the promoter or mutation of the cAMP responsive element abolished promoter activity and the binding of CREB, confirming the importance of this region and of its demethylation for fut7 transcription in T cells. Furthermore, studies on human CD4+ effector memory T cells confirmed demethylation within FUT7 corresponding to high FUT7 expression. Monocytes showed an even more extensive demethylation of the FUT7 gene whereas hepatocytes, which lack selectin ligand expression, exhibited extensive methylation. In conclusion, we show that DNA demethylation within the fut7 gene controls selectin ligand expression in mice and humans, including the inducible topographic commitment of T cells for skin and inflamed sites.

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Section: Discussionmentioning

confidence: 99%

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Pink

Ratsch

Mardahl

et al. 2016

The Journal of Immunology

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“…Although other mononuclear cells than T cells such as monocytes and dendritic cells can express CLA [19], lymphocytes expressing CLA comprised 25% of the lesion cells. This number is much lower than that observed in psoriasis, where CLA-positive cells account for up to 90% of lesion T cells [36].…”

Section: Discussionmentioning

confidence: 99%

The skin homing receptor cutaneous leucocyte-associated antigen (CLA) is up-regulated byLeishmaniaantigens in T lymphocytes during active cutaneous leishmaniasis

Mendes-Aguiar¹,

Gomes-Silva²,

Nunes

et al. 2009

Clinical and Experimental Immunology

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SummaryThe cutaneous leucocyte-associated antigen receptor (CLA) can direct Leishmania-specific T lymphocytes towards inflamed skin lesions. Homing receptors [CLA, lymphocyte-associated antigen 1 (LFA-1) or CD62L] were analysed in lymphocytes from blood and cutaneous leishmaniasis (CL) lesions. CL patients with active lesions (A-CL) presented lower levels of T lymphocytes expressing the CLA + phenotype (T CD4 + = 10·4% Ϯ 7·5% and T CD8 + = 5·8% Ϯ 3·4%) than did healthy subjects (HS) (T CD4 + = 19·3% Ϯ 13·1% and T CD8 + = 21·6% Ϯ 8·8%), notably in T CD8 + (P < 0·001). In clinically cured patients these percentages returned to levels observed in HS. Leishmanial antigens up-regulated CLA in T cells (CLA + in T CD4 + = 33·3% Ϯ 14·1%; CLA + in T CD8 + = 22·4% Ϯ 9·4%) from A-CL but not from HS. An enrichment of CLA + cells was observed in lesions (CLA + in T CD4 + = 45·9% Ϯ 22·5%; CLA + in T CD8 + = 46·4% Ϯ 16·1%) in comparison with blood (CLA + in T CD4 + = 10·4% Ϯ 7·5%; CLA + in T CD8 + = 5·8% Ϯ 3·4%). Conversely, LFA-1 was highly expressed in CD8+ T cells and augmented in CD4+ T from peripheral blood of A-CL patients. In contrast, CD62L was not affected. These results suggest that Leishmania antigens can modulate molecules responsible for migration to skin lesions, potentially influencing the cell composition of inflammatory infiltrate of leishmaniasis or even the severity of the disease.

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“…The expression of CLA on normal human lymphocytes (and malignant leukocytes) directly correlates with the functional capacity of these cells to enter skin. [1][2][3][4][5][6][7][8][9][10] Although CLA is expressed on a subset of primitive human hematopoietic progenitor cells, [35][36][37][38] as well as on dendritic cells, monocytes, and neutrophils, 12 CLA expression is conspicuously up-regulated on effector lymphocytes and on malignant cells in patients with cutaneous inflammatory disease or leukemia/lymphoma, respectively. 1,5-10,14,47-50 Therefore, targeting the expression of CLA offers an attractive therapeutic approach for controlling leukocyte migration to skin.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9][10] CLA is a sialyl Lewis X-like carbohydrate epitope displayed on the mucinlike molecule Pselectin glycoprotein ligand-1 (PSGL-1) recognized by the rat monoclonal antibody HECA-452. 2,11,12 CLA functions as the P-selectin ligand and the principal E-and L-selectin ligand on human skin-homing T cells; specifically, the presence of HECA-452 epitopes on PSGL-1 directly correlates with the capacity of skin-homing memory T cells (including skin-disease-related lymphocytes) to bind E-selectin, which is constitutively expressed on dermal microvasculature. 2,11,13 CLA-E-selectin binding interactions mediate lymphocyte trafficking to skin, and therefore, posttranslational glycosylations on skin-homing leukocytes represent a potential therapeutic target for controlling cutaneous tropism.…”

Section: Introductionmentioning

confidence: 99%

Glycosylation-dependent inhibition of cutaneous lymphocyte–associated antigen expression: implications in modulating lymphocyte migration to skin

Dimitroff

Bernacki

Sackstein

2003

Blood

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Constitutive E-selectin expression on dermal microvascular endothelial cells plays a critical role in mediating rolling adhesive interactions of human skin-homing T cells and in pathologic accumulation of lymphocytes in skin. The major E-selectin ligand on human skin-homing T cells is cutaneous lymphocyte-associated antigen (CLA), a specialized glycoform of P-selectin glycoprotein ligand-1 (PSGL-1) defined by monoclonal antibody HECA-452. Since HECA-452 reactivity, and not PSGL-1 polypeptide itself, confers the specificity of human T cells to enter dermal tissue, inhibition of HECA-452 expression is a potential strategy for modulating lymphocyte migration to skin. In this study, we examined the efficacy of several well-characterized metabolic inhibi- IntroductionTissue-specific migration of lymphocytes in neoplastic and inflammatory processes is critically dependent on the expression of cell membrane adhesion molecules that regulate adhesive interactions with target tissue endothelium. Skin disorders, including cutaneous T-cell lymphomas, cutaneous graft-versus-host disease (GVHD), and other inflammatory diseases (eg, psoriasis), are mediated by infiltrations of skin-homing T cells that express cutaneous lymphocyte-associated antigen (CLA). [1][2][3][4][5][6][7][8][9][10] CLA is a sialyl Lewis X-like carbohydrate epitope displayed on the mucinlike molecule Pselectin glycoprotein ligand-1 (PSGL-1) recognized by the rat monoclonal antibody HECA-452. 2,11,12 CLA functions as the P-selectin ligand and the principal E-and L-selectin ligand on human skin-homing T cells; specifically, the presence of HECA-452 epitopes on PSGL-1 directly correlates with the capacity of skin-homing memory T cells (including skin-disease-related lymphocytes) to bind E-selectin, which is constitutively expressed on dermal microvasculature. 2,11,13 CLA-E-selectin binding interactions mediate lymphocyte trafficking to skin, and therefore, posttranslational glycosylations on skin-homing leukocytes represent a potential therapeutic target for controlling cutaneous tropism.The ␣2,3 sialyltransferase, ST3Gal IV, and ␣1,3 fucosyltransferases, FucTIV and FucTVII, expressed in human skin-homing lymphocytes are responsible for synthesizing terminal sialofucosylations, recognized by HECA-452, that serve as E-selectinbinding determinants on PSGL-1. 14-23 These terminal sialyl Lewis X structures are expressed on poly-N-acetyllactosamines [(Gal␤1,4GlcNAc␤1,3) n ] found on core 2 serine/threonine (O)-linked glycans and asparagine (N)-linked glycans displayed by PSGL-1. [24][25][26][27][28][29][30] Although the majority of sialyl Lewis X epitopes appear to reside on PSGL-1 O-glycans, there are 3 potential sites for N-glycosylation and sialyl Lewis X decoration. 30 Consequently, interfering with the synthesis of O-glycans or N-glycans or of poly-N-acetyllactosamine structures on either O-or N-glycans (or both) would prevent the synthesis of HECA-452 epitopes and could dampen the E-selectin-binding function of PSGL-1 (CLA) on skin-homing leukocytes. The pu...

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Neutrophils, Monocytes, and Dendritic Cells Express the Same Specialized Form of PSGL-1 as Do Skin-Homing Memory T Cells: Cutaneous Lymphocyte Antigen

Cited by 49 publications

References 48 publications

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

The skin homing receptor cutaneous leucocyte-associated antigen (CLA) is up-regulated byLeishmaniaantigens in T lymphocytes during active cutaneous leishmaniasis

Glycosylation-dependent inhibition of cutaneous lymphocyte–associated antigen expression: implications in modulating lymphocyte migration to skin

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