Nielsen Morten M, Dyring-Andersen Beatrice, Schmidt Jonas D, Witherden Deborah, Lovato Paola, Woetmann Anders, Ødum Niels, Poulsen Steen S, Havran Wendy L, Geisler Carsten, Bonefeld Charlotte M
Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Skin Inflammation Pharmacology, LEO Pharma A/S, Ballerup, Denmark.
Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
J Invest Dermatol. 2015 May;135(5):1311-1319. doi: 10.1038/jid.2015.23. Epub 2015 Jan 29.
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.
角质形成细胞（KC）与皮肤驻留免疫细胞之间的相互作用在接触性超敏反应的诱导中起重要作用。一种特定的γδ T细胞亚群，称为树突状表皮T细胞（DETC），位于小鼠表皮中，并且我们最近发现，在接触性超敏反应期间，DETC以IL-1β依赖的方式被激活并产生IL-17。DETC上的各种受体，包括NKG2D，参与了DETC对肿瘤的反应以及伤口愈合过程。NKG2D的配体（NKG2DL）是应激诱导蛋白，如小鼠UL16结合蛋白样转录本1（Mult-1）、组织相容性60（H60）和视黄酸早期诱导物-1（Rae-1），在人类中则是主要组织相容性复合体（MHC）I类链相关A（MICA）、MHC I类链相关B和UL16结合蛋白。在这里，我们表明变应原上调培养的小鼠KC中NKG2DL Mult-1、H60和Rae-1以及原代人KC中MICA的表达。我们证明Mult-1在暴露于变应原的小鼠皮肤中表达。此外，我们发现小鼠表皮中绝大多数DETC以及人类皮肤归巢的皮肤淋巴细胞相关抗原阳性γδ T细胞表达NKG2D。最后，我们证明阻断NKG2D可部分抑制变应原诱导的DETC激活。这些发现表明NKG2D和NKG2DL参与变应原诱导的DETC激活，并表明NKG2D/NKG2DL途径可能是治疗接触性超敏反应的潜在靶点。
