Neutrophil cathepsin G inhibits hapten-presenting dendritic cell production of IL-12 and skewing of hapten-reactive CD4 T Cell development to IFN-γ- and IL-17-producing effector cells in allergic contact sensitivity

Abstract

Abstract Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and challenge. Sensitization of WT mice induces hapten-reactive CD8 cells producing CHS effector cytokines IFN-γ/IL-17 and IL-4-producing CD4 cells that cannot mediate CHS. Although CXCR2-dependent Gr-1+ cell recruitment into hapten challenged skin is required to direct effector CD8 T cell infiltration to elicit CHS, sensitization of CXCR2−/− mice or neutrophil-depleted WT mice induced both hapten-reactive CD4 and CD8 cells producing IFN-γ and IL-17. CD4 T cell-mediated CHS responses were not generated during hapten sensitization of neutrophil depleted WT mice treated with anti-IL-12 mAb or neutrophil depleted IL-12−/−mice. Neutrophil depletion during hapten sensitization of WT mice markedly increased numbers of IL-12-producing hapten-primed dendritic cells (DC), DC-derived p40, and T-bet-expressing CD4 T cells in the skin-draining lymph nodes. Sensitization of mice lacking the neutrophil serine protease cathepsin G induced hapten-reactive CD4 and CD8 T cells producing IFN-γ and IL-17 with elevated and elongated CHS responses to challenge. Few Gr-1+ cells were detected in the skin draining lymph nodes following senstization suggesting this regulation may not be mediated through direct Gr-1-DC interactions. In support of this, induction of CHS effector CD4 T cells producing IFN-γ in neutrophil-depleted WT mice was eliminated by subcutaneous injection of active, but not inactivated, cathepsin G during sensitization. Thus, hapten skin sensitization induces neutrophil release of cathepsin G that systemically inhibits hapten-presenting dendritic cell production of IL-12 and the development of CHS effector CD4 T cells.