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

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 602-610 ◽  
Author(s):  
Charles J. Dimitroff ◽  
Ralph J. Bernacki ◽  
Robert Sackstein
Keyword(s):  
T Cells ◽  
Human Skin ◽  
Critical Role ◽  
Metabolic Inhibitors ◽  
Lymphocyte Migration ◽  
Skin Homing ◽  
Selectin Ligand ◽  
Adhesive Interactions ◽  
Selectin Binding ◽  
Ligand Activity

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 inhibitors of glycosylation and of a novel fluorinated analog of N-acetylglucosamine (2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoro-D-glucopyranose [4-F-GlcNAc]) to alter HECA-452 expression on human CLA+ T cells and prevent cell tethering and rolling on selectins under shear stress. At concentrations that did not affect PSGL-1 expression, we found that swainsonine (inhibitor of complex-typeN-glycan synthesis) had no effect on HECA-452 expression or selectin ligand activity, whereas benzyl-O-N-acetylgalactosamide (BAG; inhibitor of O-glycan biosynthesis) ablated HECA-452 expression on PSGL-1 and significantly lowered selectin ligand activity. We found that 4-F-GlcNAc (putative inhibitor of poly-N-acetyllactosamine biosynthesis) was more potent than BAG at lowering HECA-452 expression and selectin binding. In addition, we show that 4-F-GlcNAc was directly incorporated into native CLA expressed on T cells, indicating direct inhibition on poly-N-acetyllactosamine elongation and selectin-binding determinants on PSGL-1 O-glycans. These observations establish a potential treatment approach for targeting pathologic lymphocyte trafficking to skin and indicate that 4-F-GlcNAc may be a promising agent for treatment of dermal tropism associated with malignancies and inflammatory disorders.

scholarly journals Cd44 Is a Major E-Selectin Ligand on Human Hematopoietic Progenitor Cells

2001 ◽  
Vol 153 (6) ◽  
pp. 1277-1286 ◽  
Author(s):  
Charles J. Dimitroff ◽  
Jack Y. Lee ◽  
Shahin Rafii ◽  
Robert C. Fuhlbrigge ◽  
Robert Sackstein
Keyword(s):  
Progenitor Cells ◽  
Structural Biology ◽  
Critical Role ◽  
Hematopoietic Progenitor Cells ◽  
Flow Conditions ◽  
Hematopoietic Progenitor ◽  
Selectin Ligand ◽  
Adhesive Interactions ◽  
Binding Determinants ◽  
Ligand Activity

E-selectin plays a critical role in mediating tissue-specific homing of T cells into skin, and of primitive hematopoietic progenitor cells (HPCs) into bone marrow (BM). Though it is known that a glycoform of PSGL-1 (CLA) functions as the principal E-selectin ligand on human T lymphocytes, the E-selectin ligand(s) of human HPCs has not been identified. We used a shear-based adherence assay to analyze and define the E-selectin ligand activity of membrane proteins from human HPCs. Our data show that PSGL-1 expressed on human HPCs is an E-selectin ligand, and that HPCs also express a previously unrecognized E-selectin ligand, CD44. The E-selectin ligand activity of CD44 is conferred by the elaboration of sialylated, fucosylated binding determinants on N-glycans. This glycoform of CD44 is expressed on primitive CD34+ human HPCs, but not on more mature hematopoietic cells. Under physiologic flow conditions, this molecule mediates E-selectin–dependent rolling interactions over a wider shear range than that of PSGL-1, and promotes human HPC rolling interactions on E-selectin expressed on human BM endothelial cells. These findings offer new insights into the structural biology and physiology of CD44, and into the molecular basis of E-selectin–dependent adhesive interactions that direct homing of human HPC to BM.

scholarly journals Differential L-Selectin Binding Activities of Human Hematopoietic Cell L-Selectin Ligands, HCELL and PSGL-1

2001 ◽  
Vol 276 (50) ◽  
pp. 47623-47631 ◽  
Author(s):  
Charles J. Dimitroff ◽  
Jack Y. Lee ◽  
Kenneth S. Schor ◽  
Brenda M. Sandmaier ◽  
Robert Sackstein
Keyword(s):  
Flow Chamber ◽  
Hematopoietic Cell ◽  
Shear Stresses ◽  
Parallel Plate Flow Chamber ◽  
Hematopoietic Stem ◽  
Selectin Ligands ◽  
Selectin Ligand ◽  
Structural Biochemistry ◽  
Adhesive Interactions ◽  
Selectin Binding

Expression of L-selectin on human hematopoietic cells (HC) is associated with a higher proliferative activity and a more rapid engraftment after hematopoietic stem cell transplantation. Two L-selectin ligands are expressed on human HCs, P-selectin glycoprotein ligand-1 (PSGL-1) and a specialized glycoform of CD44 (hematopoietic cell E- and L-selectin ligand, HCELL). Although the structural biochemistry of HCELL and PSGL-1 is well characterized, the relative capacity of these molecules to mediate L-selectin-dependent adhesion has not been explored. In this study, we examined under shear stress conditions L-selectin-dependent leukocyte adhesive interactions mediated by HCELL and PSGL-1, both as naturally expressed on human HC membranes and as purified molecules. By utilizing both Stamper-Woodruff and parallel-plate flow chamber assays, we found that HCELL displayed a 5-fold greater capacity to support L-selectin-dependent leukocyte adherence across a broad range of shear stresses compared with that of PSGL-1. Moreover, L-selectin-mediated leukocyte binding to immunopurified HCELL was consistently >5-fold higher than leukocyte binding to equivalent amounts of PSGL-1. Taken together, these data indicate that HCELL is a more avid L-selectin ligand than PSGL-1 and may be the preferential mediator of L-selectin-dependent adhesive interactions among human HCs in the bone marrow.

scholarly journals Acquisition of Selectin Binding and Peripheral Homing Properties by CD4+ and CD8+ T Cells

1999 ◽  
Vol 189 (11) ◽  
pp. 1765-1776 ◽  
Author(s):  
Huijuan Xie ◽  
Yaw-Chyn Lim ◽  
Francis W. Luscinskas ◽  
Andrew H. Lichtman
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Chemokine Receptors ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Effector Cells ◽  
Inflammatory Site ◽  
Selectin Ligand ◽  
Inducible Protein ◽  
Selectin Binding

Different T cell subsets exhibit distinct capacities to migrate into peripheral sites of inflammation, and this may in part reflect differential expression of homing receptors and chemokine receptors. Using an adoptive transfer approach, we examined the ability of functionally distinct subsets of T cells to home to a peripheral inflammatory site. The data directly demonstrate the inability of naive T cells and the ability of effector cells to home to inflamed peritoneum. Furthermore, interleukin (IL)-12 directs the differentiation of either CD4+ or CD8+ T cells into effector populations that expresses functional E- and P-selectin ligand and that are preferentially recruited into the inflamed peritoneum compared with T cells differentiated in the presence of IL-4. Recruitment can be blocked by anti–E- and –P-selectin antibodies. The presence of antigen in the peritoneum promotes local proliferation of recruited T cells, and significantly amplifies the Th1 polarization of the lymphocytic infiltrate. Preferential recruitment of Th1 cells into the peritoneum is also seen when cytokine response gene 2 (CRG-2)/interferon γ–inducible protein 10 (IP-10) is used as the sole inflammatory stimulus. We have also found that P-selectin binds only to antigen-specific T cells in draining lymph nodes after immunization, implying that both antigen- and cytokine-mediated signals are required for expression of functional selectin-ligand.

The interleukin-8 receptor B and CXC chemokines can mediate transendothelial migration of human skin homing T cells

1996 ◽  
Vol 26 (9) ◽  
pp. 2056-2061 ◽  
Author(s):  
Luis F. Santamaria Babi ◽  
Bernhard Moser ◽  
Maria Teresa Perez Soler ◽  
René Moser ◽  
Pius Loetscher ◽  
...  
Keyword(s):  
T Cells ◽  
Human Skin ◽  
Transendothelial Migration ◽  
Interleukin 8 ◽  
Skin Homing

scholarly journals Characterization of E‐selectin‐binding epitopes expressed by skin‐homing T cells

Immunology ◽  
1998 ◽  
Vol 94 (4) ◽  
pp. 523-528 ◽  
Author(s):  
PRIEST ◽  
BIRD ◽  
MALHOTRA
Keyword(s):  
T Cells ◽  
Skin Homing ◽  
Selectin Binding

scholarly journals A Requirement of Protein Geranylgeranylation for Chemokine Receptor Signaling and Th17 Cell Function in an Animal Model of Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Gregory Swan ◽  
Jia Geng ◽  
Eunchong Park ◽  
Quanquan Ding ◽  
John Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Cell Function ◽  
Critical Role ◽  
Immune Surveillance ◽  
Small Gtpases ◽  
Receptor Signaling ◽  
Lymphocyte Migration

Precisely controlled lymphocyte migration is critically required for immune surveillance and successful immune responses. Lymphocyte migration is strictly regulated by chemokines and chemokine receptors. Here we show that protein geranylgeranylation, a form of post-translational protein lipid modification, is required for chemokine receptor-proximal signaling. Mature thymocytes deficient for protein geranylgeranylation are impaired for thymus egress. Circulating mature T cells lacking protein geranylgeranylation fail to home to secondary lymphoid organs or to transmigrate in response to chemokines in vitro. Mechanistically, protein geranylgeranylation modifies the γ-subunits of the heterotrimeric small GTPases that are essential for chemokine receptor signaling. In addition, protein geranylgeranylation also promotes the differentiation of IL-17-producing T helper cells while inhibiting the differentiation of Foxp3+ regulatory T cells. Finally, mice with T cell lineage-specific deficiency of protein geranylgeranylation are resistant to experimental autoimmune encephalomyelitis induction. This study elucidated a critical role of protein geranylgeranylation in regulating T lymphocyte migration and function.

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