Neutrophil Cathepsin G Regulates Dendritic Cell Production of IL-12 during Development of CD4 T Cell Responses to Antigens in the Skin [ALLERGY AND OTHER HYPERSENSITIVITIES]

Contact hypersensitivity (CHS) is a CD8 T cell–mediated response to hapten skin sensitization and challenge. Sensitization of wild-type (WT) mice induces hapten-reactive effector CD8 T cells producing IFN- and IL-17– and IL-4–producing CD4 T cells that cannot mediate CHS. Although CXCR2-dependent Ly6G⁺ (neutrophil) cell recruitment into hapten-challenged skin is required to direct effector CD8 T cell infiltration into the challenge site to elicit CHS, 2,4-dinitrofluorobenezene (DNFB) sensitization of CXCR2^–/– mice and neutrophil-depleted WT mice induced both hapten-reactive CD4 and CD8 T cells producing IFN- and IL-17. CD4 T cell–mediated CHS responses were not generated during DNFB sensitization of neutrophil-depleted WT mice treated with anti–IL-12 mAb or neutrophil-depleted IL-12^–/– mice. Neutrophil depletion during DNFB sensitization of WT mice markedly increased IL-12–producing hapten-primed dendritic cell numbers in the skin-draining lymph nodes. Sensitization of mice lacking the neutrophil serine protease cathepsin G (CG)–induced hapten-reactive CD4 and CD8 T cells producing IFN- and IL-17 with elevated and elongated CHS responses to DNFB challenge. Induction of CHS effector CD4 T cells producing IFN- in neutrophil-depleted WT mice was eliminated by s.c. injection of active, but not inactivated, CG during sensitization. Thus, hapten skin sensitization induces neutrophil release of CG that systemically inhibits hapten-presenting dendritic cell production of IL-12 and the development of hapten-reactive CD4 T cells to IFN-–producing CHS effector cells.

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