TY - JOUR
T1 - IL-1β-Dependent Activation of Dendritic Epidermal T Cells in Contact Hypersensitivity
AU - Nielsen, Morten M
AU - Lovato, Paola
AU - Macleod, Amanda S
AU - Witherden, Deborah A
AU - Skov, Lone
AU - Dyring-Andersen, Beatrice
AU - Dabelsteen, Sally
AU - Woetmann, Anders
AU - Odum, Niels
AU - Havran, Wendy L
AU - Geisler, Carsten
AU - Bonefeld, Charlotte M
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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 γδ T cells, can produce IL-17. In this study, we determine the role of γδ T cells, especially dendritic epidermal T cells (DETCs), in CHS. Using a well-established model for CHS in which 2,4-dinitrofluorobenzene (DNFB) is used as allergen, we found that γδ 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 ∼50% in TCRδ-/- mice compared with wild-type mice. In accordance, DNFB-induced ear swelling was reduced by ∼50% in IL-17-/- mice. We show that DNFB triggers DETC activation and IL-1β production in the skin and that keratinocytes produce IL-1β when stimulated with DNFB. We find that DETCs activated in vitro by incubation with anti-CD3 and IL-1β 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+ γδ T cells and DETCs in the draining lymph nodes. Taken together, we show that DETCs become activated and produce IL-17 in an IL-1β-dependent manner during CHS, suggesting a key role for DETCs in CHS. The Journal of Immunology, 2014, 192: 2975-2983.
AB - 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 γδ T cells, can produce IL-17. In this study, we determine the role of γδ T cells, especially dendritic epidermal T cells (DETCs), in CHS. Using a well-established model for CHS in which 2,4-dinitrofluorobenzene (DNFB) is used as allergen, we found that γδ 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 ∼50% in TCRδ-/- mice compared with wild-type mice. In accordance, DNFB-induced ear swelling was reduced by ∼50% in IL-17-/- mice. We show that DNFB triggers DETC activation and IL-1β production in the skin and that keratinocytes produce IL-1β when stimulated with DNFB. We find that DETCs activated in vitro by incubation with anti-CD3 and IL-1β 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+ γδ T cells and DETCs in the draining lymph nodes. Taken together, we show that DETCs become activated and produce IL-17 in an IL-1β-dependent manner during CHS, suggesting a key role for DETCs in CHS. The Journal of Immunology, 2014, 192: 2975-2983.
U2 - 10.4049/jimmunol.1301689
DO - 10.4049/jimmunol.1301689
M3 - Journal article
C2 - 24600030
SN - 0022-1767
VL - 192
SP - 2975
EP - 2983
JO - Journal of immunology (Baltimore, Md. : 1950)
JF - Journal of immunology (Baltimore, Md. : 1950)
IS - 7
ER -