Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen

J Clin Invest. 2003 Oct;112(7):1008-18. doi: 10.1172/JCI19220.

Abstract

E-selectin and P-selectin on dermal postcapillary venules play critical roles in the migration of effector T cells into inflamed skin. P-selectin glycoprotein ligand-1 (PSGL-1) modified by alpha1,3-fucosyltransferase is the principal selectin ligand on skin-homing T cells and is required for effector T cell entry into inflamed skin. We have previously shown that a fluorinated analog of N-acetylglucosamine peracetylated-4-fluorinated-d-glucosamine (4-F-GlcNAc), inhibits selectin ligand expression on human T cell PSGL-1. To analyze 4-F-GlcNAc efficacy in dampening effector T cell migration to inflamed skin, we elicited allergic contact hypersensitivity (CHS) reactions in mice treated with 4-F-GlcNAc. We also investigated 4-F-GlcNAc efficacy on lymphocyte E-selectin ligand expression in LNs draining antigen-sensitized skin and on other immunological processes requisite for CHS responses. Our results showed that 4-F-GlcNAc treatment attenuated lymphocyte E-selectin ligand expression in skin-draining LNs and prevented CHS reactions. Significant reductions in inflammatory lymphocytic infiltrate were observed, while pathways related to antigenic processing and presentation and naive T cell recognition within skin-draining LNs were unaffected. These data indicate that 4-F-GlcNAc prevents CHS by inhibiting selectin ligand activity and the capacity of effector T cells to enter antigen-challenged skin without affecting the afferent phase of CHS.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylglucosamine / analogs & derivatives*
  • Acetylglucosamine / pharmacology*
  • Animals
  • Antigen Presentation / drug effects
  • Antigens, Differentiation, T-Lymphocyte
  • Antigens, Neoplasm
  • Cell Movement / drug effects
  • Dermatitis, Contact / prevention & control*
  • E-Selectin / metabolism*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • P-Selectin / metabolism
  • Skin / immunology*
  • T-Lymphocytes / physiology*

Substances

  • Antigens, Differentiation, T-Lymphocyte
  • Antigens, Neoplasm
  • CTAGE1 protein, human
  • E-Selectin
  • Membrane Glycoproteins
  • P-Selectin
  • P-selectin ligand protein
  • 2-acetamido-1,3,6-tri-O-acetyl-4-deoxy-4-fluoroglucopyranose
  • Acetylglucosamine