NKG2D-dependent activation of dendritic epidermal T cells in contact hypersensitivity

J Invest Dermatol. 2015 May;135(5):1311-1319. doi: 10.1038/jid.2015.23. Epub 2015 Jan 29.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / adverse effects
  • Animals
  • Antibodies, Anti-Idiotypic / pharmacology
  • Carrier Proteins / metabolism
  • Cell Line
  • Cells, Cultured
  • Dermatitis, Contact / etiology
  • Dermatitis, Contact / metabolism*
  • Dermatitis, Contact / pathology*
  • Disease Models, Animal
  • Female
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Langerhans Cells / metabolism*
  • Langerhans Cells / pathology*
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Minor Histocompatibility Antigens / metabolism
  • NK Cell Lectin-Like Receptor Subfamily K / antagonists & inhibitors
  • NK Cell Lectin-Like Receptor Subfamily K / drug effects
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Nuclear Matrix-Associated Proteins / metabolism
  • Nucleocytoplasmic Transport Proteins / metabolism

Substances

  • Allergens
  • Antibodies, Anti-Idiotypic
  • Carrier Proteins
  • Histocompatibility Antigens Class I
  • KLRK1 protein, human
  • Klrk1 protein, mouse
  • MHC class I-related chain A
  • Membrane Proteins
  • Minor Histocompatibility Antigens
  • NK Cell Lectin-Like Receptor Subfamily K
  • Nuclear Matrix-Associated Proteins
  • Nucleocytoplasmic Transport Proteins
  • Rae1 protein, mouse
  • UL16 binding protein 1, mouse
  • minor H antigen H60