IL-17 Amplifies Human Contact Hypersensitivity by Licensing Hapten Nonspecific Th1 Cells to Kill Autologous Keratinocytes

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Abstract
Th17 is a newly identified lineage of effector T cells involved in autoimmunity and immune responses to pathogens. We demonstrate in this study the pathogenic role of IL-17–producing CD4+ T lymphocytes in allergic contact dermatitis (ACD) to skin-applied chemicals. IL-17+ T cells infiltrate ACD reactions and predominantly distribute at the site of heavy spongiosis. Skin IL-17+ T cells were functionally and phenotypically heterogeneous: although pure Th17 prevailed in ACD skin, hapten responsiveness was restricted to Th1/IL-17 (IFN-γ+IL-17+) and Th0/IL-17 (IFN-γ+IL-17+IL-4+) fractions, and to lesser extent Th2/IL-17 cells. In the IFN-γ–dominated ACD environment, IL-17–releasing T cells affect immune function of keratinocytes by promoting CXCL8, IL-6, and HBD-2 production. In addition, compared with Th1, supernatants from Th1/IL-17 T cells were much more efficient in inducing ICAM-1 expression on keratinocytes and keratinocyte–T cell adhesiveness in vitro. As a consequence, exposure to combined IFN-γ and IL-17 rendered keratinocytes susceptible to ICAM-1–dependent Ag nonspecific T cell killing. Thus, IL-17 efficiently amplifies the allergic reaction by rendering virtually all of the T lymphocytes recruited at the site of skin inflammation capable to directly contribute to tissue damage.