Involvement of an NKG2D Ligand H60c in Epidermal Dendritic T Cell-Mediated Wound Repair

Abstract

Dendritic epidermal T cells (DETCs) found in mouse skin are NKG2D-positive γδ T cells involved in immune surveillance and wound repair. It is assumed that the interaction of an NKG2D receptor on DETCs and an MHC class I-like NKG2D ligand on keratinocytes activates DETCs, which then secrete cytokines promoting wound repair. However, direct evidence that DETC activation through NKG2D signaling promotes wound repair is not available. In the present study, we generated mAbs for an NKG2D ligand H60c previously suggested to be expressed specifically on skin keratinocytes. Local administration of H60c-specific mAb inhibited activation of DETCs and significantly delayed wound repair. Likewise, administration of NKG2D-specific mAb impaired wound repair to a similar extent. The delay in wound closure resulting from the blockade of the NKG2D pathway was comparable to that observed in γδ T cell-deficient mice. These results indicate that H60c/NKG2D interactions play a critical role in wound repair. Reassessment of binding affinities showed that H60c monomers bind to NKG2D with affinity (Kd = 26 ± 3.2 nM) comparable to those of other high-affinity NKG2D ligands. H60c is transcribed not only in skin but also in tissues such as tongue and female reproductive tract known to contain epithelium-resident γδ T cells expressing invariant TCRs, suggesting a more general role for H60c in the maintenance of epithelial integrity.

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].…”

Innate and Adaptive Immune Responses in Wound Epithelialization

“…TCR-specific activation is pivotal to DETC function during cutaneous wound repair. 50 Published studies have identified NKG2D, 51 JAML, 52 and CD100 (Sema 4D) 47 as co-stimulatory molecules for DETC, known to interact with damaged keratinocytes in response to wounding (Fig. 4).…”

Differential Requirements of TCR Signaling in Homeostatic Maintenance and Function of Dendritic Epidermal T Cells

“…We propose that TCR signaling at the wound edge may be responsible for a delay in dendrite contraction so that DETCs have enough time to secrete cytokines and growth factors before entering proliferative phase. The rounding behavior in response to wounding is most likely regulated by other signaling events, such as NKG2D, JAML, CD100, working in parallel with TCR signals(39–42). …”