TNF-α Induces Endothelial Cell Expression of Intercellular Adhesion Molecule-1 (ICAM-1) Required for Recruitment of Antigen-Primed CD8 T Cells to Mediate Responses in the Skin (44.2)

Abstract

Abstract Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten sensitization and challenge of the skin. Elicitation of CHS is initiated when hapten-primed CD8 T cells producing IFN-γ and IL-17 traffic to the challenge site and simulate endothelial cells (EC) to produce CXCL1/KC. KC is required for the neutrophil recruitment directing CD8 T cell infiltration through the EC where they are activated to induce the edema of CHS. Factors required for this KC production were tested. Hapten-immune CD8 T cells stimulated hapten-labeled EC to produce KC in vitro and this was blocked by antibodies to IFN-γ, IL-17, and ICAM-1 but not to TNFa. Immunohistochemical staining and qRT-PCR analyses indicated that hapten challenge induced ICAM-1 expression on skin challenge site EC and TNFa expression in both naïve and sensitized mice within 4 hrs of hapten challenge. Transfer of hapten-primed T cells to naïve wild-type but not ICAM-1 knockout mice induced KC production at 6 hrs after hapten challenge. In vivo treatment with antibodies to TNF-α or to ICAM-1 at the time of hapten challenge eliminated KC production, neutrophil infiltration, and CHS. Anti-TNF-α mAb significantly reduced ICAM-1 as well as IFN-γ, and IL-17 mRNA expression in the challenged skin of sensitized mice. Thus, hapten challenge stimulates TNFα production that induces the EC expression of ICAM-1 required for hapten-primed T cells activation to produce the IFN-γ and IL-17 that induces the EC to produce KC.