NKG2D-Dependent Activation of Dendritic Epidermal T Cells in Contact Hypersensitivity

• DOI: 10.1038/jid.2015.23
• Publication Date: 2015-01-29T14:44:35Z
• Authors: Morten M. Nielsen; Beatrice Dyring-A...; Jonas D. Schmidt; Deborah Witherden; Paola Lovato; Anders Woetmann; Niels Ødum; Steen S. Poulsen; Wendy L. Havran; Carsten Geisler; Charlotte M. Bone...
• Keywords: Keratinocytes; 0301 basic medicine; Nucleocytoplasmic Transport Proteins; Dermatology; Dermatitis, Contact; Biochemistry; Article; Cell Line; Minor Histocompatibility Antigens; Mice; 03 medical and health sciences; 0302 clinical medicine; Nuclear Matrix-Associated Proteins; Animals; Humans; 10. No inequality; Molecular Biology; Cells, Cultured; Histocompatibility Antigens Class I; Membrane Proteins; Cell Biology; Allergens; 6. Clean water; Antibodies, Anti-Idiotypic; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; NK Cell Lectin-Like Receptor Subfamily K; Langerhans Cells; Female; Carrier Proteins

The interaction between keratinocytes (KCs) and skin-resident immune cells has an important role in induction of contact hypersensitivity. A specific subset of γδ T cells termed dendritic epidermal T cells (DETCs) are located in mouse epidermis, and we have recently shown that DETCs become activated and produce IL-17 in an IL-1β-dependent manner during contact hypersensitivity. Various receptors on DETCs, including NKG2D, are involved in DETC responses against tumors and during wound healing. The ligands for NKG2D (NKG2DL) are stress-induced proteins such as mouse UL16-binding protein-like transcript 1 (Mult-1), histocompatibility 60 (H60), and retinoic acid early inducible-1 (Rae-1) in mice and major histocompatibility complex (MHC) class I-chain-related A (MICA), MHC class I-chain-related B, and UL16-binding protein in humans. Here, we show that allergens upregulate expression of the NKG2DL Mult-1, H60, and Rae-1 in cultured mouse KCs and of MICA in primary human KCs. We demonstrate that Mult-1 is expressed in mouse skin exposed to allergen. Furthermore, we find that the vast majority of DETCs in murine epidermis and skin-homing cutaneous lymphocyte-associated antigen positive γδ T cells in humans express NKG2D. Finally, we demonstrate that blocking of NKG2D partially inhibits allergen-induced DETC activation. These findings demonstrate that NKG2D and NKG2DL are involved in allergen-induced activation of DETCs and indicate that the NKG2D/NKG2DL pathway might be a potential target for treatment of contact hypersensitivity.