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T-Cell-Mediated Injury to Keratinocytes: Insights from Animal Models of the Lichenoid Tissue Reaction

  • Jan P. Dutz
    Correspondence
    Department of Dermatology and Skin Science, Skin Care Center, University of British Columbia, 835 West Tenth Avenue, Vancouver BC, Canada V5Z 4E8
    Affiliations
    Department of Dermatology and Skin Science, Skin Care Center, University of British Columbia, Vancouver, BC, Canada
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      The lichenoid tissue reaction is a histopathologic pattern of skin inflammation noted in a diverse group of clinical diseases. Although few of these diseases are reflected in animal models, select murine models of skin inflammation recapitulate salient characteristics of the lichenoid tissue reaction pattern. Animal models of predominantly T-cell-mediated skin inflammation induced by the adoptive transfer of T-cell clones, by the generation of autoreactive T-cell receptor transgenic T cells, and by genetic manipulation of the epidermis are reviewed. Their relevance for a better understanding of the lichenoid tissue reaction is discussed.

      Abbreviations

      FDE
      fixed drug eruption
      GVHD
      graft versus host disease
      OVA
      ovalbumin
      TEN
      toxic epidermal necrolysis
      TLR
      toll-like receptor

      Introduction: Definition and Scope of the Problem

      The lichenoid tissue reaction (LTR) or interface dermatitis is a specific pattern of skin injury that is common to multiple disease processes. Unifying concepts behind this injury reaction pattern were identified by careful histologic analysis and include (1) epidermal cell damage with prominent keratinocyte cell death most pronounced at the basal-cell layer; (2) the subsequent formation of Civatte bodies in the epidermis and colloid bodies in the dermis; and (3) a prominent mixed mononuclear cell infiltrate at the dermoepidermal junction that “obscures the junction” (
      • Ragaz A.
      • Ackerman A.B.
      Evolution, maturation, and regression of lesions of lichen planus. New observations and correlations of clinical and histologic findings.
      ;
      • Sontheimer R.D.
      • Gilliam J.N.
      Immunologically mediated epidermal cell injury.
      ;
      • Weedon D.
      The lichenoid tissue reaction.
      ). The nomenclature and nosology of the LTR-interface dermatitis pattern is well described in an accompanying article by
      • Sontheimer R.D.
      • Gilliam J.N.
      Immunologically mediated epidermal cell injury.
      . The diseases that share this histologic reaction pattern have been classified into those with a prominent cellular infiltrate at the dermoepidermal junction (termed “cell rich”) and those with a sparse cellular infiltrate, despite evidence of basilar keratinocyte damage (termed ‘cell poor’). Diseases exemplifying the cell-rich LTR include lichen planus, fixed drug eruption (FDE), and toxic epidermal necrolysis (TEN). Diseases exemplifying cell-poor LTR include cutaneous lupus erythematosus, cutaneous dermatomyositis, and the cutaneous manifestations of graft-versus-host disease (GVHD). Features of cell-poor LTR are also shared by lichen sclerosus, morphea, and vitiligo whereas features of cell-rich LTR (apoptosis and mononuclear cell infiltrate) are also seen in alopecia areata. The multiplicity of clinical manifestations of this reaction pattern is thus broad and presents a challenge to the biologist tasked to explain mechanistic differences and similarities between these conditions. Nevertheless, a study of the commonalities between these conditions promises to reveal important principles of skin biology.

      The Evolution of the Lichenoid Tissue Reaction: Principles for the Study of Animal Models

      Careful analysis of biopsy specimens of lichen planus to assess the histologic correlates of evolution, maturation, and regression demonstrated that epidermal dendritic cells or Langerhans cells increase in numbers early in disease, followed by the appearance of lymphocytes at the epidermodermal junction, keratinocyte death, and eventual hyperplasia (
      • Ragaz A.
      • Ackerman A.B.
      Evolution, maturation, and regression of lesions of lichen planus. New observations and correlations of clinical and histologic findings.
      ). The concept that an autoimmune attack by T cells upon the epidermis represents the primary pathologic event in the LTR (reviewed by
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ) eventually followed these observations. Study of established clinical disease in humans obscures the potential initiating events in the disease process. One way of circumventing this limitation in humans, as pioneered by Shiohara, is the study of FDEs. These eruptions are elicited by specific drug exposure, demonstrate a typical pattern of lichenoid inflammation, and moreover, manifest a “recall response” where previously affected but clinically normal skin develops recurrent lesions after drug challenge (
      • Shiohara T.
      • Mizukawa Y.
      Fixed drug eruption: a disease mediated by self-inflicted responses of intraepidermal T cells.
      ).
      The predictable recurrence of lesions following drug challenge has allowed the histologic analysis of preclinical lesions within hours of drug challenge. Even before rechallenge, a slight increase in lymphocyte numbers is detected at the dermoepidermal interface when compared to previously uninvolved skin. Immunohistochemical analysis has identified a predominance of CD8+ T cells within this prechallenge epidermis whereas CD4+ T cells predominate in the perivascular and dermal compartments. The epidermal cells express CD45RA and CD11b, consistent with an effector memory phenotype and the skin homing markers CLA and αEβ7 (
      • Mizukawa Y.
      • Yamazaki Y.
      • Teraki Y.
      • Hayakawa J.
      • Hayakawa K.
      • Nuriya H.
      • et al.
      Direct evidence for interferon-gamma production by effector-memory-type intraepidermal T cells residing at an effector site of immunopathology in fixed drug eruption.
      ). These cells also express the early activation marker CD69 but not CD25, suggesting the possibility of a low level of ongoing stimulation, possibly from self-antigen. Within 3 hours of drug administration, the CD8+ T cells migrate from intraepidermal locations to the basal epidermis, and produce the inflammatory cytokine interferon-γ. Simultaneously, CD4+ T cells begin to accumulate at the dermoepidermal junction. Analysis of active FDE lesions has revealed that the activation of the intraepidermal CD8+ T cells is associated with the apoptotic death of keratinocytes manifested by keratinocyte-specific caspase-3 expression and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining (
      • Choi H.J.
      • Ku J.K.
      • Kim M.Y.
      • Kang H.
      • Cho S.H.
      • Kim H.O.
      • et al.
      Possible role of Fas/Fas ligand-mediated apoptosis in the pathogenesis of fixed drug eruption.
      ). The keratinocytes are induced to express Fas and the mononuclear cell infiltrate to express FasL providing a possible upstream mechanism for the induction of apoptosis.
      TEN is a more severe form of LTR with the induction of significant epidermal damage. Roujeau and colleagues have characterized this form of drug-induced skin damage (
      • Nassif A.
      • Bensussan A.
      • Boumsell L.
      • Deniaud A.
      • Moslehi H.
      • Wolkenstein P.
      • et al.
      Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells.
      ). Analysis of T cells within the blister fluid obtained from lesions demonstrates a preponderance of CD8+ T cells that demonstrate drug-specific perforin and granzyme-mediated cytotoxicity toward keratinocytes. A comparison of these two forms of drug-mediated LTR reveals that different cytotoxic mechanisms may be involved as the CD8+ T cells in FDE rarely express granzyme. Further, CD4+CD25+ IL-10-secreting regulatory T cells are prominent in FDE lesions, possibly limiting epidermal damage (
      • Teraki Y.
      • Shiohara T.
      IFN-gamma-producing effector CD8+ T cells and IL-10-producing regulatory CD4+ T cells in fixed drug eruption.
      ) but are not detected in TEN.
      Keratinocytes likely participate in the onset of LTRs and the recruitment of T cells into the epidermis as induction of basal keratinocyte expression of intracellular adhesion molecule 1, a molecule that promotes T-cell adhesion, and migration has been noted in lichen planus and cutaneous lupus erythematosus (
      • Bennion S.D.
      • Middleton M.H.
      • David-Bajar K.M.
      • Brice S.
      • Norris D.A.
      In three types of interface dermatitis, different patterns of expression of intercellular adhesion molecule-1 (ICAM-1) indicate different triggers of disease.
      ). Thus a careful analysis of human LTR tissues has revealed that common events in the pathogenesis of lesions include the activation of skin dendritic cells, keratinocytes, the recruitment and activation of CD8+ and CD4+ T cells, followed by cytotoxic keratinocyte damage and possibly regulatory T-cell-mediated resolution of lesions (Figure 1). Further analysis of the cellular phenotypes accompanying these reactions and the cytokines- and chemokines-mediating cell behavior in these reactions is the subject of current human-based research summarized by (

      Meller S, Gilliet M, Homey B. Chemokines in the pathogenesis of lichenoid tissue reactions. J Invest Dermatol (in press)

      ) and (
      • Wenzel J.
      • Tüting T.
      An IFN-Associated cytotoxic cellular immune response against Viral, Self- or Tumor antigens is a common pathogenetic feature in “Interface Dermatitis”.
      ) at the “Lichenoid Tissue Reaction” session of the 2007 Montagna Symposium. Credible animal models must recapitulate and build upon these findings. Select murine models that fulfill these criteria are presented herein.
      Figure thumbnail gr1
      Figure 1Essential components of the lichenoid tissue reaction. Common events in the lichenoid tissue reaction include activation of skin dendritic cells and keratinocytes, recruitment and activation of CD4 and CD8 T cells, followed by cytotoxic damage to keratinocytes with release of keratinocyte antigens in the form of Civatte bodies or colloid bodies.

      LTR Induction by Autoreactive T Cell Clones

      To study the potential role of CD4+ T cells in the genesis of the LTR,
      • Shiohara T.
      • Moriya N.
      • Mochizuki T.
      • Nagashima M.
      Lichenoid tissue reaction (LTR) induced by local transfer of Ia-reactive T-cell clones. II. LTR by epidermal invasion of cytotoxic lymphokine-producing autoreactive T cells.
      generated autoreactive T-cell clones from the skin-draining lymph nodes of mice immunized with the purified protein derivative of mycobacterium tuberculosis. These clones responded to self class II major histocompatibility complex molecules by producing both lymphotoxin and interferon-γ. Injection of these clones into the footpads of mice produced a delayed-type hypersensitivity reaction with infiltration of the T cells into the epidermis, consequent keratinocyte class II major histocompatibility complex expression, and an LTR with Civatte body formation and satellite cell necrosis. This demonstrated that T-cell reactivity for autologous class II major histocompatibility complex was sufficient to induce an LTR. It is assumed that the generation of autoreactive T-cell clones was a by-product of the immune response to purified protein derivative in the donor mice and the autoreactive nature of these cells, as well as the lack of bacterial adjuvant in the transfer system, likely determines the focal nature of the LTR response. Study of heterologous human lymphocytes injected into human skin xenografted upon immunodeficient mice revealed that migration of activated interferon-γ-producing CD8+ T cells into the skin mediated apoptotic damage of keratinocytes (
      • Christofidou-Solomidou M.
      • Albelda S.M.
      • Bennett F.C.
      • Murphy G.F.
      Experimental production and modulation of human cytotoxic dermatitis in human–murine chimeras.
      ). Again, induction of epidermal intracellular adhesion molecule 1 expression was noted, recapitulating the observations in patients. This work demonstrated clearly that alloreactive human CD8+ T cells may also induce an LTR.

      Models of LTR with Defined Antigens

      The generation of T-cell receptor transgenic mice has allowed the production of animals that may provide a ready source of naive T cells specific for defined antigens. This tool, when combined with animals expressing defined antigens in the skin by means of skin-specific genetic promoters, has allowed the detailed study of the role of self-reactive T cells in the generation of LTR in mice. Expression of the model antigen chicken ovalbumin (OVA) in a membrane-bound form by keratinocytes in the epidermis and hair follicles has been achieved using the keratin 5 promoter (K5 mOVA mice;
      • Azukizawa H.
      • Kosaka H.
      • Sano S.
      • Heath W.R.
      • Takahashi I.
      • Gao X.H.
      • et al.
      Induction of T-cell-mediated skin disease specific for antigen transgenically expressed in keratinocytes.
      ). When these mice receive an infusion of OVA-specific CD8+ T cells, the T cells home to the epidermis and follicular epithelium as well as the dermis. This is associated with the appearance of deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive apoptotic keratinocytes but little clinical disease. When host T cells are depleted, either by sublethal irradiation or by the athymic (nude) genetic phenotype, a spontaneous clinical disease with liquefaction of basal cells, blister formation, and inflammatory degeneration of hair follicles reminiscent of TEN develops. Bone marrow transplant experiments demonstrated that bone-marrow-derived antigen-presenting cells (presumably dendritic cells) with the appropriate major histocompatibility complex were required to activate the CD8+ T cells. The requirement of T-cell depletion for full disease expression suggested the presence of a population of regulatory T cells competent in the downregulation of the inflammatory response.
      To further identify the regulatory T cells limiting CD8+ T-cell-mediated damage to the epidermis,
      • Azukizawa H.
      • Sano S.
      • Kosaka H.
      • Sumikawa Y.
      • Itami S.
      Prevention of toxic epidermal necrolysis by regulatory T cells.
      generated mice that expressed both the OVA antigen in the skin and OVA-specific CD8+ T cells. These mice were tolerant of the self-antigen expressed in the skin. However, when the investigators depleted the CD4+ T cells from these mice, or in the absence of a thymus (where endogenous regulatory T cells generated), severe skin inflammation reminiscent of TEN developed. The transfer of a CD4+CD25+ subset of regulatory T cells prevented the expression of disease when these cells were cotransferred with dendritic cells (
      • Azukizawa H.
      • Sano S.
      • Kosaka H.
      • Sumikawa Y.
      • Itami S.
      Prevention of toxic epidermal necrolysis by regulatory T cells.
      ). These experiments demonstrate that a severe form of LTR (TEN-like disease), mediated by CD8+ T cells, can be controlled by CD4+CD25+ regulatory T cells and that dendritic cells are required for the activation of these regulatory cells.
      The adoptive transfer experiments of
      • Shiohara T.
      • Moriya N.
      • Mochizuki T.
      • Nagashima M.
      Lichenoid tissue reaction (LTR) induced by local transfer of Ia-reactive T-cell clones. II. LTR by epidermal invasion of cytotoxic lymphokine-producing autoreactive T cells.
      demonstrated that activated clones of self-reactive CD4+ T cells are capable of inducing an LTR. Naive self-reactive CD4+ T cells may likewise induce disease. The adoptive transfer of OVA-specific CD4+ T cells into mice expressing soluble OVA and otherwise deficient in T cells because of an absence of RAG resulted in epidermal cell apoptosis and marked dermal/epidermal T-cell infiltration characteristic of acute GVHD (
      • Knoechel B.
      • Lohr J.
      • Kahn E.
      • Bluestone J.A.
      • Abbas A.K.
      Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen.
      ). These mice recover from this inflammatory skin disease within 2–3 weeks. FoxP3 is a transcription factor well associated with a regulatory phenotype in CD4+ T cells. The recovery from disease in these mice is associated with the generation of OVA-specific T-cell receptor bearing CD4+CD25+ markers and expressing the FoxP3 transcription factor. Thus, either self-reactive CD8+ T cells or CD4+ T cells may induce LTRs and both forms of disease are susceptible to modulation by regulatory T cells. Regulatory T cells are not the only modulators of the LTR as autoreactive T-cell deletion (
      • Waithman J.
      • Allan R.S.
      • Kosaka H.
      • Azukizawa H.
      • Shortman K.
      • Lutz M.B.
      • et al.
      Skin-derived dendritic cells can mediate deletional tolerance of class I-restricted self-reactive T cells.
      ) and anergy induction (
      • Mayerova D.
      • Wang L.
      • Bursch L.S.
      • Hogquist K.A.
      Conditioning of Langerhans cells induced by a primary CD8 T cell response to self-antigen in vivo.
      ) within the skin-draining lymph nodes have also been noted coincident with disease resolution.
      With either CD4+ or CD8+ self-reactive T cells, a TH1 pattern of inflammation with T-cell-derived interferon-γ production has been described. IL-17 is a previously unidentified proinflammatory cytokine that participates in T-cell-mediated skin inflammation such as contact hypersensitivity (
      • Nakae S.
      • Komiyama Y.
      • Nambu A.
      • Sudo K.
      • Iwase M.
      • Homma I.
      • et al.
      Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses.
      ). The tissue inflammation in CD4+ T-cell-mediated acute GVHD to soluble OVA is IL-17 dependent as an antibody to IL-17 was able to improve inflammatory skin scores and alopecia in this model (
      • Lohr J.
      • Knoechel B.
      • Wang J.J.
      • Villarino A.V.
      • Abbas A.K.
      Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease.
      ). The importance of IL-17 in the pathogenesis of psoriasis has been recently underscored (
      • Zaba L.C.
      • Cardinale I.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • Suarez Farinas M.
      • Fuentes-Duculan J.
      • et al.
      Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses.
      ). However, the relevance of this concept to the LTR remains to be more fully explored.

      Models of Spontaneous LTR: The Roles of Dendritic Cells and Keratinocytes

      The analysis of immune responses to artificial self-antigens as described above has revealed that bone-marrow-derived antigen-presenting cells are required for the activation of the T cells to skin-derived antigens (
      • Azukizawa H.
      • Kosaka H.
      • Sano S.
      • Heath W.R.
      • Takahashi I.
      • Gao X.H.
      • et al.
      Induction of T-cell-mediated skin disease specific for antigen transgenically expressed in keratinocytes.
      ). Overexpression of CD40 ligand, a costimulatory molecule for dendritic cells, within the epidermis is sufficient to induce systemic autoimmunity with autoantibodies and features of graft-versus-host-like LTR (
      • Mehling A.
      • Loser K.
      • Varga G.
      • Metze D.
      • Luger T.A.
      • Schwarz T.
      • et al.
      Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.
      ). This disease is associated with recruitment of dendritic cells within the skin-draining lymph nodes and with the activation of pathogenic CD8+ T cells that infiltrate the skin and are able to induce disease when transferred into healthy hosts. This observation demonstrates that keratinocyte-mediated activation of skin dendritic cells can initiate both an LTR and systemic autoimmunity. Both epidermal Langerhans cells and dermal dendritic cells have been shown to acquire keratinocyte-derived antigens and prime CD8+ T cells to these antigens within the skin-draining lymph nodes (
      • Waithman J.
      • Allan R.S.
      • Kosaka H.
      • Azukizawa H.
      • Shortman K.
      • Lutz M.B.
      • et al.
      Skin-derived dendritic cells can mediate deletional tolerance of class I-restricted self-reactive T cells.
      ). Dermal dendritic cells have been recently shown to promote cellular immune reactions to epidermal antigen independently of epidermal Langerhans cells (
      • Bursch L.S.
      • Wang L.
      • Igyarto B.
      • Kissenpfennig A.
      • Malissen B.
      • Kaplan D.H.
      • et al.
      Identification of a novel population of Langerin+ dendritic cells.
      ;
      • Ginhoux F.
      • Collin M.P.
      • Bogunovic M.
      • Abel M.
      • Leboeuf M.
      • Helft J.
      • et al.
      Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state.
      ;
      • Poulin L.F.
      • Henri S.
      • de Bovis B.
      • Devilard E.
      • Kissenpfennig A.
      • Malissen B.
      The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells.
      ). The relative roles of dermal versus epidermal dendritic cells in inducing LTRs remain to be explored.

      Models of altered type 1 interferon signaling

      Human observational data have strongly implicated type 1 interferon signaling, type 1 interferon inducible genes, and the activation of cutaneous plasmacytoid dendritic cells in lichen planus, the prototypic LTR (
      • Wenzel J.
      • Scheler M.
      • Proelss J.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated cytotoxic inflammation in lichen planus.
      ,
      • Wenzel J.
      • Peters B.
      • Zahn S.
      • Birth M.
      • Hofmann K.
      • Kusters D.
      • et al.
      Gene expression profiling of lichen planus reflects CXCL9+-mediated inflammation and distinguishes this disease from atopic dermatitis and psoriasis.
      ). The role of type 1 interferons and plasmacytoid dendritic cells remains less explored in animal models of LTR. Mice deficient in the interferon regulatory factor-2 exhibit enhanced type 1 interferon responses leading to a CD8+ T-cell dependent inflammatory disease (
      • Hida S.
      • Ogasawara K.
      • Sato K.
      • Abe M.
      • Takayanagi H.
      • Yokochi T.
      • et al.
      CD8(+) T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-alpha/beta signaling.
      ). These mice showed erythema, hair loss, and ulceration that were manifested histopathologically as keratinocyte activation with intracellular adhesion molecule 1 expression and basilar CD4+ and CD8+ T-cell infiltration. Despite an absence of detectable increases in interferon-α or -β, interferon-related genes such as 2′5′-oligoadenylate synthetase were increased within the skin and genetic blockade of interferon signaling abolished the disease. Downstream interferon-γ production by the activated memory CD8+ T cells (
      • Arakura F.
      • Hida S.
      • Ichikawa E.
      • Yajima C.
      • Nakajima S.
      • Saida T.
      • et al.
      Genetic control directed toward spontaneous IFN-alpha/IFN-beta responses and downstream IFN-gamma expression influences the pathogenesis of a murine psoriasis-like skin disease.
      ) was critical for disease induction in this model.

      KC activation and LTR

      Keratinocytes are fully competent immune players (
      • Kupper T.S.
      The activated keratinocyte: a model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses.
      ) and cross talk between keratinocytes and lymphocytes may modulate inflammatory skin disease (
      • Rebholz B.
      • Haase I.
      • Eckelt B.
      • Paxian S.
      • Flaig M.J.
      • Ghoreschi K.
      • et al.
      Crosstalk between keratinocytes and adaptive immune cells in an IkappaBalpha protein-mediated inflammatory disease of the skin.
      ). Keratinocyte-derived IL-1-β and tumor-necrosis factor-α are well-known inducers of dendritic cell activation and migration. Overexpression of tumor-necrosis factor-α in the skin induces a GVHD-like phenotype (
      • Cheng J.
      • Turksen K.
      • Yu Q.C.
      • Schreiber H.
      • Teng M.
      • Fuchs E.
      Cachexia and graft-vs-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice.
      ). Overexpression of IL-1 within the skin results not only in epidermal hyperplasia, but in a monocyte-rich inflammatory infiltrate within the dermis (
      • Groves R.W.
      • Mizutani H.
      • Kieffer J.D.
      • Kupper T.S.
      Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 alpha in basal epidermis.
      ). Overexpression of interferon-γ within the skin results in increased epidermal cell death, dermal LTR-like inflammation, hair loss, hypopigmentation, and lupus-like systemic autoimmunity (
      • Carroll J.M.
      • Crompton T.
      • Seery J.P.
      • Watt F.M.
      Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss.
      ;
      • Seery J.P.
      • Carroll J.M.
      • Cattell V.
      • Watt F.M.
      Antinuclear autoantibodies and lupus nephritis in transgenic mice expressing interferon gamma in the epidermis.
      ). Which stimuli induce cytokine production within the epidermis? TLRs are pathogen recognition molecules expressed by keratinocytes (
      • Kollisch G.
      • Kalali B.N.
      • Voelcker V.
      • Wallich R.
      • Behrendt H.
      • Ring J.
      • et al.
      Various members of the Toll-like receptor family contribute to the innate immune response of human epidermal keratinocytes.
      ;
      • Lebre M.C.
      • van der Aar A.M.
      • van Baarsen L.
      • van Capel T.M.
      • Schuitemaker J.H.
      • Kapsenberg M.L.
      • et al.
      Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.
      ) as well as Langerhans cells (
      • Renn C.N.
      • Sanchez D.J.
      • Ochoa M.T.
      • Legaspi A.J.
      • Oh C.K.
      • Liu P.T.
      • et al.
      TLR activation of Langerhans cell-like dendritic cells triggers an antiviral immune response.
      ). Stimulation of epidermal TLR by pathogens or endogenous ligands released through physical or drug-mediated skin damage may participate in the initiation of keratinocyte and dendritic cells activation preceding the development of LTRs (
      • Sugita K.
      • Kabashima K.
      • Atarashi K.
      • Shimauchi T.
      • Kobayashi M.
      • Tokura Y.
      Innate immunity mediated by epidermal keratinocytes promotes acquired immunity involving Langerhans cells and T cells in the skin.
      ). Local inflammation may also be required to permit the recruitment of previously activated T cells into the skin. Study of acute GVHD in murine bone marrow chimeras has shown that local skin inflammation subsequent to TLR activation (for example by the topical application of the TLR7 agonist imiquimod) is required for the local induction of cutaneous GVHD (
      • Chakraverty R.
      • Cote D.
      • Buchli J.
      • Cotter P.
      • Hsu R.
      • Zhao G.
      • et al.
      An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues.
      ). Interestingly, dendritic cells within the skin-draining lymph node maintain a normal phenotype in the absence of TLR signaling and in germ-free mice, suggesting that other stimuli or endogenous genetic programs mediate constitutive dendritic cell activation (
      • Wilson N.S.
      • Young L.J.
      • Kupresanin F.
      • Naik S.H.
      • Vremec D.
      • Heath W.R.
      • et al.
      Normal proportion and expression of maturation markers in migratory dendritic cells in the absence of germs or Toll-like receptor signaling.
      ). A candidate for such a stimulus is the inflammasome, a multimeric molecular complex that controls the activation of caspase-1 (
      • Ogura Y.
      • Sutterwala F.S.
      • Flavell R.A.
      The inflammasome: first line of the immune response to cell stress.
      ) and that is present in keratinocytes (
      • Watanabe H.
      • Gaide O.
      • Petrilli V.
      • Martinon F.
      • Contassot E.
      • Roques S.
      • et al.
      Activation of the IL-1beta-processing inflammasome is involved in contact hypersensitivity.
      ). In favor of this hypothesis, uric acid, a potential endogenous activator of the inflammasome enhances skin-draining lymph node activation and skin-directed T-cell predominant immune responses (
      • Liu L.
      • Inoue H.
      • Nakayama H.
      • Kanno R.
      • Kanno M.
      The endogenous danger signal uric acid augments contact hypersensitivity responses in mice.
      ).
      Whereas plasmacytoid dendritic cells are known to produce large amounts of type 1 interferons, other sources of these cytokines may be important in LTRs. Direct type 1 interferon production by keratinocytes has been noted in human LTRs such as lichen planus (
      • Wenzel J.
      • Peters B.
      • Zahn S.
      • Birth M.
      • Hofmann K.
      • Kusters D.
      • et al.
      Gene expression profiling of lichen planus reflects CXCL9+-mediated inflammation and distinguishes this disease from atopic dermatitis and psoriasis.
      ), and cutaneous lupus erythematosus (
      • Reefman E.
      • Kuiper H.
      • Limburg P.C.
      • Kallenberg C.G.
      • Bijl M.
      Type I interferons are involved in the development of UVB-induced inflammatory skin lesions in systemic lupus erythematosus (SLE) patients.
      ). Keratinocytes can be induced to produce type 1 interferons by the TLR3 ligand double-stranded viral RNA with consequent conditioning of dendritic cells to promote TH1 T-cell activation (
      • Liu L.
      • Inoue H.
      • Nakayama H.
      • Kanno R.
      • Kanno M.
      The endogenous danger signal uric acid augments contact hypersensitivity responses in mice.
      ). The regulation of keratinocyte production of interferons and other inflammatory mediators and subsequent effects in the induction and promotion of the LTR using murine models with defined self-antigens or models of GVHD remains areas worthy of investigation.

      Modeling Therapy in Mice

      As dendritic cells likely orchestrate the initiation of T-cell-mediated immune responses such as LTR, a better understanding of the effects of current therapies for the LTR upon these cells is required. The animal models described may provide convenient systems for this reexamination. Antimalarial drugs such as quinacrine are effective against cutaneous lupus erythematosus, dermatomyositis, and GVHD. One major mode of action of these drugs is now felt to be the inhibition of endosomal TLR (TLR3, 7, 8, and 9) signaling (reviewed by
      • Kalia S.
      • Dutz J.P.
      New concepts in antimalarial use and mode of action in dermatology.
      ). Quinacrine has been recently shown to inhibit Langerhans cell migration in response to haptens through the downregulation of NF-κB and consequent tumor-necrosis factor-α, IL-1, and CCL21 release in the skin (
      • Gorbachev A.V.
      • Gasparian A.V.
      • Gurova K.V.
      • Gudkov A.V.
      • Fairchild R.L.
      Quinacrine inhibits the epidermal dendritic cell migration initiating T cell-mediated skin inflammation.
      ). Calcineurin inhibition is effective in the treatment of severe lichen planus. Likewise, established autoimmunity induced by overexpression of CD40L within the skin can be controlled by FK506 (
      • Loser K.
      • Balkow S.
      • Higuchi T.
      • Apelt J.
      • Kuhn A.
      • Luger T.A.
      • et al.
      FK506 controls CD40L-induced systemic autoimmunity in mice.
      ). Although this is was felt to be mediated primarily through the drug's effects upon T cells, calcineurin inhibitors have been recently shown to have profound effects upon the activation state of dendritic cells in vivo (
      • Haider A.S.
      • Lowes M.A.
      • Suarez-Farinas M.
      • Zaba L.C.
      • Cardinale I.
      • Khatcherian A.
      • et al.
      Identification of cellular pathways of “Type 1,” Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine a in psoriasis.
      ). A better understanding of the manipulation of dendritic cells may enable the generation of regulatory T cells specifically tailored to inhibit LTR. Ex vivo generated regulatory T cells are able to control established autoimmunity in the CD40L transgenic mice (
      • Loser K.
      • Hansen W.
      • Apelt J.
      • Balkow S.
      • Buer J.
      • Beissert S.
      In vitro-generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity.
      ). Protein and peptide vaccination through UV-irradiated skin may be used to generate antigen-specific regulatory T cells capable of inhibiting the priming and reactivation of CD8+ T cells directly in vivo (
      • Ghoreishi M.
      • Dutz J.P.
      Tolerance induction by transcutaneous immunization through ultraviolet-irradiated skin is transferable through CD4+CD25+ T regulatory cells and is dependent on host-derived IL-10.
      ). More efficient and cost-effective strategies to induce antigen-specific regulatory T cells need to be developed and tested.

      Concluding Comments

      Animal models of disease are almost always imperfect. This is also true for the group of diseases that give rise to LTRs. For example, no representative animal models exist for lichen planus, the prototypical LTR, or for dermatomyositis. Animal models for the cutaneous forms of lupus erythematosus are imperfect (
      • Furukawa F.
      Photosensitivity in cutaneous lupus erythematosus: lessons from mice and men.
      ). By reducing the LTR to the essential components and surveying the literature, the author has compiled and described murine models that shed light upon crucial elements of the LTR (summarized in Table 1). We hope that readers/investigators will be stimulated to use these models as a point of departure to further clarify the mechanisms that initiate and perpetuate diseases resulting from T-cell assault upon the epidermis.
      Table 1Murine models used in the generation and study of therapy of lichenoid tissue reactions
      T cells as mediators
       • Adoptive transfer of autoreactive CD4 T cells (
      • Shiohara T.
      • Moriya N.
      • Mochizuki T.
      • Nagashima M.
      Lichenoid tissue reaction (LTR) induced by local transfer of Ia-reactive T-cell clones. II. LTR by epidermal invasion of cytotoxic lymphokine-producing autoreactive T cells.
      )
       • Adoptive transfer of alloreactive CD8 T cells (
      • Christofidou-Solomidou M.
      • Albelda S.M.
      • Bennett F.C.
      • Murphy G.F.
      Experimental production and modulation of human cytotoxic dermatitis in human–murine chimeras.
      )
      Manipulation of keratinocyte antigen expression
       • Keratin-promoter-driven antigen expression (
      • Azukizawa H.
      • Kosaka H.
      • Sano S.
      • Heath W.R.
      • Takahashi I.
      • Gao X.H.
      • et al.
      Induction of T-cell-mediated skin disease specific for antigen transgenically expressed in keratinocytes.
      )
       • Ubiquitous soluble antigen expression (
      • Knoechel B.
      • Lohr J.
      • Kahn E.
      • Bluestone J.A.
      • Abbas A.K.
      Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen.
      )
      Immune activation within the epidermis
       • CD40 ligand expression by keratinocytes (
      • Mehling A.
      • Loser K.
      • Varga G.
      • Metze D.
      • Luger T.A.
      • Schwarz T.
      • et al.
      Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.
      )
       • Epidermal overexpression of TNF-α (
      • Cheng J.
      • Turksen K.
      • Yu Q.C.
      • Schreiber H.
      • Teng M.
      • Fuchs E.
      Cachexia and graft-vs-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice.
      )
       • Epidermal overexpression of IL-1 (
      • Groves R.W.
      • Mizutani H.
      • Kieffer J.D.
      • Kupper T.S.
      Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 alpha in basal epidermis.
      )
       • Epidermal overexpression of IFN-γ (
      • Carroll J.M.
      • Crompton T.
      • Seery J.P.
      • Watt F.M.
      Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss.
      )
       • Manipulation of the skin in models of graft-versus-host disease (
      • Chakraverty R.
      • Cote D.
      • Buchli J.
      • Cotter P.
      • Hsu R.
      • Zhao G.
      • et al.
      An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues.
      ), topical TLR7 agonist administration
      Therapy of lichenoid tissue reactions
       • Calcineurin inhibition (
      • Loser K.
      • Balkow S.
      • Higuchi T.
      • Apelt J.
      • Kuhn A.
      • Luger T.A.
      • et al.
      FK506 controls CD40L-induced systemic autoimmunity in mice.
      )
       • Regulatory T-cell therapy (
      • Loser K.
      • Hansen W.
      • Apelt J.
      • Balkow S.
      • Buer J.
      • Beissert S.
      In vitro-generated regulatory T cells induced by Foxp3-retrovirus infection control murine contact allergy and systemic autoimmunity.
      )

      ACKNOWLEDGMENTS

      Jan P Dutz is supported by a Senior Scholar Award of the Michael Smith Foundation for Health Research and by the Children and Family Research Institute.

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