CCR5 chemokine receptor mediates recruitment of MHC class II-positive Langerhans cells in the mouse corneal epithelium

Invest Ophthalmol Vis Sci. 2005 Apr;46(4):1201-7. doi: 10.1167/iovs.04-0658.


Purpose: To characterize the chemokines and chemokine receptors that mediate the effect of proinflammatory cytokines, interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, on the recruitment of MHC class II(+) Langerhans cells (LCs) in the corneal epithelium.

Methods: A standard model for corneal LC recruitment, application of cautery to the central corneal surface was used, and the differential gene expression levels of a panel of chemokines and chemokine receptors were determined by RNase protection assay. Chemokine receptor-knockout mice were used to evaluate the recruitment of MHC class II(+) LCs to the corneal epithelium. To determine the sensitivity of selected chemokines to IL-1 and TNF-alpha stimulation, the chemokine gene expression pattern was analyzed after blockade of IL-1 and TNF receptors.

Results: CCR1, -2, and -5 were overexpressed in corneas after cauterization. Topical administration of soluble TNF receptor I and IL-1 receptor antagonist, which abrogated corneal LC recruitment, significantly suppressed the gene transcription levels of the ligands of CCR1 and/or -5, regulated on activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta. The recruitment of major histocompatibility complex (MHC) class II(+) LC was significantly suppressed in CCR5(-/-) mice and blockade of RANTES and MIP-1beta, but not in CCR1(-/-), CCR2(-/-)/MIP-1alpha(-/-), or MIP-1alpha(-/-) mice. The evaluation of epithelial CD11c(+) LC cells by confocal microscopy revealed coexpression for CCR5 primarily among B7(-) (CD80(-)/CD86(-)) subsets of these LCs but not among the mature B7(+) subsets of CD11c(+) LCs.

Conclusions: These data suggest that CCR5 plays a critical role in mediating recruitment and mobilization of MHC class II(+) LCs into the corneal epithelium. Targeting CCR5 and its ligands may be a new strategy for modulating immunity.

Publication types

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

MeSH terms

  • Animals
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CCL5 / metabolism
  • Epithelium, Corneal / physiology*
  • Gene Expression
  • Histocompatibility Antigens Class II / metabolism*
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1 / pharmacology
  • Langerhans Cells / physiology*
  • Macrophage Inflammatory Proteins / metabolism
  • Major Histocompatibility Complex / physiology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CCR1
  • Receptors, CCR2
  • Receptors, CCR5 / physiology*
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
  • Sialoglycoproteins / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology


  • Ccr1 protein, mouse
  • Ccr2 protein, mouse
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CCL5
  • Histocompatibility Antigens Class II
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Macrophage Inflammatory Proteins
  • Receptors, CCR1
  • Receptors, CCR2
  • Receptors, CCR5
  • Receptors, Chemokine
  • Receptors, Tumor Necrosis Factor, Type I
  • Sialoglycoproteins
  • Tumor Necrosis Factor-alpha