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

Abstract

The interaction between keratinocytes (KC) and skin-resident immune cells plays an important role in induction of contact hypersensitivity (CHS). A specific subset of γδ T cells termed dendritic epidermal T cells (DETC) are located in mouse epidermis, and we have recently shown that DETC become activated and produce IL-17 in an IL-1β-dependent manner during CHS. Various receptors on DETC, including NKG2D, are involved in DETC responses against tumors and during wound healing. The ligands for NKG2D (NKG2DL) are stress-induced proteins such as Mult-1, H60, Rae-1 in mice and MICA, MICB and ULBP in humans. Here, we show that allergens up-regulate expression of the NKG2DL Mult-1, H60 and Rae-1 in cultured mouse KC and of MICA in primary human KC. We demonstrate that Mult-1 is expressed in mouse skin exposed to allergen. Furthermore, we find that the vast majority of DETC in murine epidermis and skin-homing cutaneous lymphocyte-associated antigen (CLA) 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 DETC and indicate that the NKG2D/NKG2DL pathway might be a potential target for treatment of CHS.

Accumulation and activation of epidermal γδ T cells in a mouse model of chronic dermatitis is not required for the inflammatory phenotype

“…The early and progressive upregulation of several NKG2D ligands, such as H60c [43,44], Rae-1 [45], and Mult1 [46] in the epidermis of K5-R1/R2 mice might be responsible for the activation of DETCs. In support of this hypothesis, induced expression of Rae-1 in the skin lead to CD69 upregulation and a rounded shape of DETCs [29], injection of antiH60c blocking antibody inhibited DETC activation after wounding [47], and Mult-1 blockade partially inhibited allergen-induced DETC activation [48]. We also detected increased expression of Plexin B2, a CD100 receptor ligand that is upregulated in response to cellular stress and induces DETC rounding [49].…”

“…2015. 45: 2517-2528 upregulation and a rounded shape of DETCs [29], injection of antiH60c blocking antibody inhibited DETC activation after wounding [47], and Mult-1 blockade partially inhibited allergen-induced DETC activation [48]. We also detected increased expression of Plexin B2, a CD100 receptor ligand that is upregulated in response to cellular stress and induces DETC rounding [49].…”

Differential effect of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) on leukocyte infiltration during contact hypersensitivity responses

“…Many of them also expressed NKG2D, and NKG2D played a role in the activation cycle (Nielsen et al, 2015). More recently, the contribution of Vγ4 T cells in the response to DNFB and subsequent neutrophil infiltration was elegantly mapped out by Jiang et al (2017).…”

Emerging Skin T-Cell Functions in Response to Environmental Insults

“…DETCs develop in the embryonic thymus and express an invariant VΓ3Vδ1TCR, yet the antigen of the DETC remains elusive. In addition, DETCs also express natural killer group receptor 2D (NKG2D) and can receive signals from NKG2D ligands, expressed by stressed keratinocytes (Nielsen et al, 2015; Strid et al, 2008). In a steady state, DETCs form polarized immunologic synapses that anchor to keratinocyte tight junctions and likely provide TCR-mediated signals for maintenance in the skin (Chodaczek et al, 2012).…”

“…Similar to DETCs, dermal Γδ T cells display an activated memory-like CD44 + CD69 + CD103 + phenotype;however, they express variant Γδ TCR chains, with some preference for VΓ4 (Sumaria et al, 2011). DETCs require TCR (co-)stimulation, dermal Γδ T cells are highly “innate” and sensitive to cytokine and pathogen-associated molecular pattern recognition (MacLeod et al, 2013; Nielsen et al, 2014, 2015; Strid et al, 2008; Witherden et al, 2010, 2012). Whereas DETCs are dependent on both IL-7 and IL-15 for survival and maintenance, Vγ4 + dermal γδ T cells are largely dependent on IL-7 but not IL-15.…”