Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 7, Pages 2975-2983Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1301689
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Funding
- LEO Pharma Research Foundation
- A.P. Moller Foundation for the Advancement of Medical Sciences
- Kongelig Hofbuntmager Aage Bangs Fond
- Danish Medical Research Council
- Novo Nordisk Foundation
- Lundbeck Foundation
- National Institutes of Health [AI36964, AI64811, T32AI004244]
- Novo Nordisk Fonden [NNF12OC0002036] Funding Source: researchfish
- The Danish Cancer Society [R72-A4571] Funding Source: researchfish
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Substances that penetrate the skin surface can act as allergens and induce a T cell-mediated inflammatory skin disease called contact hypersensitivity (CHS). IL-17 is a key cytokine in CHS and was originally thought to be produced solely by CD4(+) T cells. However, it is now known that several cell types, including gamma delta T cells, can produce IL-17. In this study, we determine the role of gamma delta T cells, especially dendritic epidermal T cells (DETCs), in CHS. Using a well-established model for CHS in which 2,4-dinitro-fluorobenzene (DNFB) is used as allergen, we found that gamma delta T cells are important players in CHS. Thus, more IL-17-producing DETCs appear in the skin following exposure to DNFB in wild-type mice, and DNFB-induced ear swelling is reduced by similar to 50% in TCR delta(-/-) mice compared with wild-type mice. In accordance, DNFB-induced ear swelling was reduced by similar to 50% in IL-17(-/-) mice. We show that DNFB triggers DETC activation and IL-1 beta production in the skin and that keratinocytes produce IL-1 beta when stimulated with DNFB. We find that DETCs activated in vitro by incubation with anti-CD3 and IL-1 beta produce IL-17. Importantly, we demonstrate that the IL-1R antagonist anakinra significantly reduces CHS responses, as measured by decreased ear swelling, inhibition of local DETC activation, and a reduction in the number of IL-17(+) gamma delta T cells and DETCs in the draining lymph nodes. Taken together, we show that DETCs become activated and produce IL-17 in an IL-1 beta-dependent manner during CHS, suggesting a key role for DETCs in CHS.
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