Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes - Detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161

Background: The genetic and immunological basis for psoriasis is unknown. T hrough the use of a severe combined immunodeficient mouse-human skin model, T cells have been shown to induce psoriasis, which points to a pathologica l role for such immunocompetent cells. During ongoing studies using this mo del, a previously overlooked subset of immunocytes expressing receptors typ ically present on natural killer (NK) cells was discovered, which may shed new light on the genetic susceptibility for psoriasis. Observations: Immunocytes from a psoriatic patient were injected into engra fted allogeneic normal human skin and produced a psoriatic plaque. Moreover , the disturbed epidermal environment spread to induce a greater than 20-fo ld increase in thickness of adjacent mouse epidermis with prominent elongat ion of rete pegs. Thus, rather than observing the predicted graft-vs-host r eaction in the allogeneic human or xenogeneic mouse skin, injection of psor iatic immunocytes triggered psoriasis. To explore a potential mechanism to explain the lack of cytopathic effect by psoriatic T cells, immunostaining to detect inhibitory receptors normally present on NK cells was performed. These receptors include surface molecules that can inhibit NK cell prolifer ation, cytokine release, and/or cytotoxicity tie, killer cell inhibitory re ceptors [KIRs]), as well as those that may activate NK cell cytotoxicity ti e, killer cell activating receptors [KARs]). The blood-derived psoriatic im munocytes in the skin graft expressed CD94, CD158a, CD158b, NKB1, and CD161 . Furthermore, both hyperplastic human and murine keratinocytes express the major histocompatibility complex (MHC) class I-like CD1d protein, which ha s been shown to be a specific ligand of T cells expressing CD161 and other NK cell-associated receptors. Conclusions: Since several KIRs and KARs are known to recognize various cla ss I MHC alleles, and because psoriasis inheritance and susceptibility has been linked to various class I MHC molecules, we propose a novel hypothesis in which the pathogenic T cells are postulated to express an assortment of KIRs and KARs. These interactions may produce direct activation without an y exogenous antigen, and at the same time block the cytotoxic effector func tion of these activated immunocytes in this allogeneic and xenogeneic exper imental setting. In addition, human T cells expressing CD161 may be capable of interacting with human and murine CD1d expressed by the epidermal kerat inocytes. These unexpected findings demonstrate that psoriasis is an immuno logical disease in which pathogenic T cells rather than epidermal keratinoc ytes are of primary importance. Functional studies will determine if target ing this previously overlooked population of immunocytes with blocking reag ents will generate a novel immunotherapeutic strategic pathway for psoriasi s, and whether disease susceptibility and/or incidence patterns can be expl ained by genetic abnormalities involving these ligand-receptor interactions .