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1From The Laboratory of Immunology, Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts; the 2Department of Corneal Tissue Regeneration, University of Tokyo Graduate School of Medicine, Tokyo, Japan; the 3Department of Pathology, University of North Carolina, Chapel Hill, North Carolina; and 4The Perlmutter Laboratory, Children’s Hospital, Harvard Medical School, Boston, Massachusetts.
PURPOSE. To characterize the chemokines and chemokine receptors that mediate the effect of proinflammatory cytokines, interleukin (IL)-1 and tumor necrosis factor (TNF)-
, 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- 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)-1, and MIP-1ß. The recruitment of major histocompatibility complex (MHC) class II+ LC was significantly suppressed in CCR5–/– mice and blockade of RANTES and MIP-1ß, but not in CCR1–/–, CCR2–/–/MIP-1–/–, or MIP-1–/– 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.
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