CCR5 Chemokine Receptor Mediates Recruitment of MHC Class II-Positive Langerhans Cells in the Mouse Corneal Epithelium

Abstract

purpose. To characterize the chemokines and chemokine receptors that mediate the effect of proinflammatory cytokines, interleukin (IL)-1 and tumor necrosis factor (TNF)-α, 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-α 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)-1α, and MIP-1β. The recruitment of major histocompatibility complex (MHC) class II+ LC was significantly suppressed in CCR5−/− mice and blockade of RANTES and MIP-1β, but not in CCR1−/−, CCR2−/−/MIP-1α−/−, or MIP-1α−/− 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.