CD1d-dependent, iNKT-cell cytotoxicity against keratinocytes in allergic contact dermatitis

Conventional CD8+ T-lymphocytes are thought to be major effector cells in allergic contact dermatitis (ACD). However, previous work has demonstrated a significant population of invariant natural killer T-cells (iNKT-cells) in the elicitation phase of ACD. In this study, we investigate whether iNKT-cells have the capacity to serve as effector lymphocytes in ACD. Using in situ staining of skin biopsy specimens from ACD lesions, we observed intra-epidermal iNKT-cells. Presence of these cells provides the possibility of interactions with keratinocytes (KC), Langerhans cells (LC) and CD1d-bearing antigen-presenting cells (APC). Investigation into gene expression profiles of cytotoxic effector molecules in seven different cases of ACD found that the expression of perforin and granzymes A, B and K were significantly elevated in ACD relative to paired clinically normal skin. Immunostaining of ACD skin biopsy specimens revealed that these cytotoxic granules indeed localized to iNKT-cells. Studies of antigen presentation of KC to iNKT-cells show that these epithelial cells do not activate the expression of cytotoxicity effector genes in resting iNKT-cells, but had the capacity to serve as targets for activated iNKT-cells, which was dependent on CD1d expression. Mature LC were not able to present glycolipids to iNKT-cells and did not up-regulate CD1d in vitro to a variety of maturational stimuli or in vivo during ACD. These data suggest that iNKT-cells can serve as effector cells during human ACD and provide the rationale for developing inhibitory glycolipids as therapeutic agents for ACD.