Characterization of a T cell line bearing natural killer receptors and capable of creating psoriasis in a SCID mouse model system
Introduction
Psoriasis is a common disorder (affecting 2–3% of the population world-wide) triggered when activated immunocytes infiltrate the skin, subsequently inducing prominent epidermal thickening and angiogenesis [1]. The nature of the inciting antigen, and phenotype of the pathogenic immunocyte, remain important unresolved issues. Another frequently asked question regarding psoriasis is the identity and localization of the gene or genes responsible for the familial transmission and inheritance pattern of psoriasis [2]. Progress in addressing these important issues has been hampered by the lack of a suitable animal model. To fill this experimental void, a research tool was created for investigation of psoriasis by engrafting human skin onto SCID mice, followed by creation of bona fide psoriatic plaques using activated immunocytes [3], [4], [5], [6].
As the SCID mouse/human skin animal experimental system has been shown to produce stable phenotypes, validated from a pharmacological perspective, and found to be a reproducible model by several groups [7], [8], [9], it is now possible to explore the identity of the pathogenic immunocyte. Recently, the initial observation that activated peripheral blood-derived mononuclear cells (including T cells, B cells, monocytes, dendritic cells, etc.) can cause psoriasis using the animal model, was confirmed and extended with highly purified T cell lines [6]. When CD4+ T cell lines, but not CD8+ T cell lines, were injected into engrafted pre-psoriatic skin, typical psoriatic plaques were created [6].
During the aforementioned studies using the SCID mouse model, the presence of a previously overlooked subset of T cells was discovered in skin-namely T cells that also express receptors present on natural killer (NK) cells, especially CD161 (NKR-P1A) and other C-type lectin molecules such as CD94 [5], [6]. Moreover, the ligands for these receptors include class I MHC antigens and may also extend to class I-like molecules such as CD1d, which were identified in psoriatic lesions [5]. The nosological relationship between the T cells bearing NKRs as seen in psoriasis, with the classical NK-T cells previously characterized in mice and men, is currently unclear. Classical NK-T cells express an invariant T cell receptor (Vα14-Jα281 paired with Vβ8,2 or 7 in mouse) together with NK cell receptors (NKR-P1 and Ly-49 in mouse), as described by many groups of investigators [10], [11], [12], [13], [14]. While most mature T cells express either CD4 or CD8 coreceptors, NK-T cells in certain organ sites such as thymus or liver are generally either CD4+ or are double negative for CD4 and CD8 [12].
Abnormalities of NK-T cells have been linked to several autoimmune diseases, especially insulin-dependent diabetes mellitus [15], [16], [17]. In these diseases, NK-T cells primarily function in an immunoregulatory fashion by modulating the activity of pathogenic T cells by producing cytokines such as IL-4. However, whether NK-T cells can themselves have a direct pathogenic role in producing disease is not clear. To determine the immunological significance of T cells bearing NK receptors in psoriasis, a CD161+/CD94+ cell line was established from the peripheral blood of a psoriatic patient. In-vitro, this T cell line produced large amounts of IFN-γ and IL-13 when incubated with keratinocytes induced to express CD1d. This response was blocked by a CD1d specific mAb indicating that the T cells directly recognized CD1d. Previous investigators have documented that injection of IFN-γ into skin induced psoriatic lesions [18]. Upon injection into engrafted pre-psoriatic skin, this CD3+/CD4+/CD94+/CD161+ T cell line produced a plaque with all of the clinical, histological and immunophenotypic characteristics of psoriasis. In this report the phenotype of the pathogenic T cell line is presented, as well as cellular and molecular characteristics of the acutely created psoriatic plaque. Thus, this NK receptor-bearing T cell line appears to play a role different from that previously postulated for classical NK-T cells in autoimmune disease [15], [16], [17]. Such conventional NK-T cells were conspicuous by their absence in the latter case, whereas in this model system the CD94+/CD161+ T cells were conspicuous by their presence as pathogenic effector cells that triggered a cascade of events leading to a Th1-type cytokine network response in-vivo.
Section snippets
Patient
The NK receptor bearing T cell line was established from the circulation of a previously untreated psoriatic patient who was otherwise healthy. After obtaining informed consent, a keratome sample was obtained from uninvolved skin. At the time of sampling, the patient had approximately 20% of her body covered with typical psoriatic plaques particularly evident on her elbows and forearms.
Human skin/SCID mouse chimera and tissue processing
A human skin xenograft of uninvolved skin was orthotopically transplanted onto an 8-week-old C.B.17-SCID mouse
Generation and phenotype of a NK receptor bearing T cell line isolated from a psoriatic patient
A stable T cell line was isolated from peripheral blood lymphocytes of a psoriatic patient by serial restimulation with bacterial superantigens and IL-2. Prior to injection into the engrafted autologous uninvolved skin, the cell line was immunophenotyped using a panel of mAbs. Fig. 1 reveals that over 90% of the cells were CD3+ and CD4+ with only rare (<1%) CD8+ cells. By 2-color staining and FACS analysis this CD3+/CD4+ T cell line contained 51% CD161+ cells and 39% CD94+ cells. However, these
Discussion
Psoriasis, like other inflammatory diseases, including organ-specific autoimmune diseases such as diabetes mellitus, is characterized by pathogenic T cells that create a Th1 type cytokine network in the lesional tissue site [1], [25], [26], [27]. In this report, a pathogenic T cell line expressing CD161 and CD94 was propagated from the blood of a psoriatic patient. This T cell line was reactive towards CD1d expressed by either keratinocytes or HeLa cells. In contrast to previous studies using
Acknowledgements
The authors thank Patricia Bacon for performing immunohistochemical staining, Jeff Panella for performing the RPAs, and Heide Bauer and Crystal Tabor for manuscript and figure preparation. Drs Kevin Cooper and Zsuzsanna Bata-Csorgo (Case Western Reserve University) kindly provided the IFN-γ producing CD4+ T cell clones 4F4 and 4F1. This work was supported by NIH Grant AR40065 (B.J. Nickoloff).
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These three authors contributed equally to this work.