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Peripheral CD8+ T Cell Tolerance Against Melanocytic Self-Antigens in the Skin Is Regulated in Two Steps by CD4+ T Cells and Local Inflammation: Implications for the Pathophysiology of Vitiligo

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Peripheral CD8+ T Cell Tolerance Against Melanocytic Self-Antigens in the Skin Is Regulated in Two Steps by CD4+ T Cells and Local Inflammation: Implications for the Pathophysiology of Vitiligo
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  See related Commentary on page xiii Peripheral CD8 þ  T Cell Tolerance Against Melanocytic Self-Antigens in the Skin Is Regulated in Two Steps by CD4 þ  T Cellsand Local Inflammation: Implications for the Pathophysiologyof Vitiligo Julia Steitz, Ju ¨ rgen Bru ¨ ck, Julia Lenz, Steffi Bu ¨ chs, and Thomas Tu ¨ ting Laboratory of Experimental Dermatology, Department of Dermatology, University of Bonn, Bonn, Germany Experimental evidence has suggested a role for CD8 þ  cytotoxic T lymphocytes (CTL) in the pathophysiology of vitiligo, a pigmentation disorder with focal loss of melanocytes in the skin. The discovery of tyrosinase-relatedprotein 2 (TRP2) as a model melanocytic self-antigen recognized by CD8 þ  CTL in C57BL/6 mice allowed us toanalyze the requirements for CD8 þ  T cell-mediated autoimmune destruction of melanocytes in an experimentalmodel. Using two different genetic methods for the induction of cellular immunity  in vivo , gene gun bombardmentoftheskinand injection ofrecombinantadenovirus,weshowthatperipheral toleranceofCD8 þ  T cellsrecognizinga single TRP2-derived H2-K b -binding peptide is regulated in two steps. In the induction phase, stimulation andexpansion of TRP2-specific CD8 þ  T cells  in vivo  depend on CD4 þ  T cell help. In the effector phase, autoimmunedestruction of melanocytes in the skin depends on local inflammation. Our results suggest that accidental stim-ulation of CD8 þ  CTL recognizing major histocompatibility complex class I-binding peptides derived from me-lanocytic proteins in the context of an inflammatory skin disease may play an important role in the pathophysiologyof vitiligo. Key words: CD8 þ  T cells/immune tolerance/melanocytes/TRP2/vitiligoJ Invest Dermatol 124:144–150, 2005Vitiligo is a common pigmentation disorder where me-lanocytes are focally destroyed in the skin. The associationwith other autoimmune diseases suggests immunologicalpathomechanisms in vitiligo (Berd  et al,  1996; Dittmar andKahaly, 2003). To support this hypothesis, autoantibodies tomelanosomal proteins such as the tyrosinase family of en-zymes have been detected in the serum of patients withvitiligo (Song  et al  , 1994; Cui and Bystryn, 1995; Baharav et al  , 1996; Fishman  et al  , 1997; Kemp  et al  , 1997). Morerecently, autoreactive CD8 þ  cytotoxic T lymphocytes(CTL), which specifically recognize melanocytic differentia-tion antigens, were demonstrated in perilesional skin and inthe peripheral blood (Ogg  et al  , 1998; Lang  et al  , 2001; LeGal  et al  , 2001; Palermo  et al  , 2001; Mandelcorn-Morson et al  , 2003). Melanocyte-specific CTL have been identifiedin patients with melanoma where vitiligo may occur duringimmunotherapeutic intervention (Scheibenbogen  et al  ,1994; Rosenberg and White, 1996; Rosenberg, 1997; Oka-moto  et al  , 1998). Importantly, adoptive transfer of me-lanoma antigen-specific cytotoxic T lymphocytes may beassociated with the regression of melanoma metastasesand the appearance of vitiligo, thus providing direct evi-dence of Tcell-mediated vitiligo in humans (Yee  et al  , 2000;Dudley  et al  , 2002).Experiments in murine models were also able to dem-onstrate that CD8 þ  CTL recognizing shared lineage-spe-cific melanocytic self-antigens such as tyrosinase or thetyrosinase-related protein 2 (TRP2) can cause autoimmunedestruction of melanocytes leading to vitiligo-like furdepigmentation (Bowne  et al  , 1999; Overwijk  et al  , 1999;Colella  et al  , 2000; Steitz  et al  , 2000). The inductionand regulation of melanocyte-specific CTL are not wellunderstood. Clearly, mechanisms maintaining peripheralself-tolerance must control potentially autoreactive, me-lanocyte-specific CTL  in vivo . This could be directly dem-onstrated by immunization of tyrosinase gene knockoutalbino and wild-type mice against the enzyme tyrosinasewhere strong CTL responses could be stimulated in tyros-inase-deficient mice, whereas only very weak reactivity wasobserved in wild-type mice (Colella  et al  , 2000). Our grouppreviously reported that the  in vivo  induction of TRP2-spe-cific CD8 þ  T cells using novel genetic immunization tech-niques was only successful when TRP2 was linked toforeign helper determinants (Steitz  et al  , 2002).In this study, we wished to analyze the requirements forCD8 þ  T cell-mediated autoimmune destruction of me-lanocytes in C57BL/6 mice in greater detail. Using the genegun and recombinant adenoviruses—two fundamentallydifferent genetic approaches for the induction of cellularimmunity  in vivo —we provide evidence that peripheral tol-erance of CD8 þ  CTL recognizing melanocytic self antigensis regulated in two steps: (1) the primary stimulation of   Abbreviations: Ad, recombinant adenovirus; EGFP, enhancedgreen fluorescent protein; TRP2, tyrosinase-related protein 2 Copyright r 2004 by The Society for Investigative Dermatology, Inc. 144  potentially autoreactive CD8 þ  T cells in the lymphoid sys-tem depends on CD4 þ  T cell help in the induction phaseand (2) the local autoimmune destruction of melanocytes inthe skin requires a strong inflammatory stimulus in the ef-fector phase. Results Construction of expression plasmids encoding fusionproteins between enhanced green fluorescent protein(EGFP) and defined amino acid sequences of murineTRP2  We previously showed that effective stimulation of TRP2 aa180–188  peptide-specific CD8 þ  T cells with geneticimmunization strategies required linkage of the weaklyimmunogenic TRP2 with strong helper determinants. Fol-lowing bombardment of the abdominal skin with plasmidDNA encoding a fusion protein between TRP2 and theimmunogenic marker protein EGFP using the gene gun, weobserved  in vivo  stimulation and expansion of TRP2 aa180–188 peptide-specific CD8 þ  T cells associated with vitiligo-likefur depigmentation (Steitz  et al  , 2002). In contrast, immu-nization with unmodified murine TRP2 only very rarely in-duced significant Tcell reactivity or coat color changes. Butin these experiments we could not establish a direct rela-tionship between TRP2 aa180–188  peptide-specific CD8 þ  Tcells and vitiligo because full-length TRP2 encoding aa30–519 fused in frame to EGFP was used for immunization. Tospecifically address the role of CD8 þ  T cells recognizingthe TRP2 aa180–188  peptide for the induction of autoimmunevitiligo, we then constructed plasmid DNA encoding fusionproteins between EGFP and the truncated sequencesaa30–188, aa30–179, or aa180–188 of murine TRP2 (Fig1  A  ). These fragments of TRP2 were generated by PCR, se-quenced to exclude mutations, joined in frame to the C-terminal end of EGFP, and inserted into an expressionplasmid containing a CMV immediate-early promotor andan SV40 polyadenylation signal. Expression of EGFP by allconstructs was confirmed in transiently transfected 293 cells in vitro  by fluorescence microscopy. Additionally, the size of the fusion proteins was verified by western blot analyses of lysates from transiently transfected 293 cells (Fig 1 B  ). Stimulation of CD8 þ  T cells  in vivo  and induction of autoimmune vitiligo following gene gun immunizationwith plasmid DNA containing a single H2-K b -bindingpeptide derived from the melanocytic protein TRP2  Insubsequent experiments, we tested the newly constructedexpression plasmids encoding the various fusion proteinsfor their ability to stimulate TRP2 aa180–188  peptide-specificCD8 þ  T cells  in vivo  and induce autoimmune vitiligo inthe skin. Groups of 6 C57BL/6 mice were shaved onthe abdomen and bombarded with the expression plasm-ids pCMV-EGFP.TRP2 aa30–519 , pCMV-EGFP.mTRP2 aa30–188 ,pCMV-EGFP.mTRP2 aa30–179 , pCMV-EGFP.mTRP2 aa180–188 ,or pCMV-EGFP using the gene gun on a weekly basis for5 wk. Two mice of each group were sacrificed 1 wk after thefifth immunization to analyze induction of antigen-specificCTL  in vivo . To this end, we tested splenocytes in interferon(IFN) g -ELISPOT assays for recognition of the synthetic H2-K b -binding peptides TRP2 aa180–188  and medium control. As expected, immunization with plasmid DNA encodingthe truncated fusion proteins EGFP.mTRP2 aa30–188  orEGFP.mTRP2 aa180–188  stimulated TRP2 aa180–188  peptide-specific CD8 þ  T-cells  in vivo  as effective as immunizationwith plasmid DNA encoding full-length EGFP.TRP2 aa30–519 (Fig 2  A  ). The remaining four mice of each group were mon-itored for the appearance of fur depigmentation. All micethat had been immunized with plasmid DNA containing theimmunogenic EGFP and the TRP2 aa180–188  peptide eventu-ally developed autoimmune vitiligo on the site of gene gunbombardment on the abdomen within a few weeks after thelast immunization (Fig 2 B  and  C   ). Importantly, bombardmentof the skin with the plasmid expressing the TRP2 aa180–188 peptide epitope attached to the C-terminus of EGFP effec-tively induced vitiligo-like coat color changes, demonstrat-ing that CD8 þ  T cells specific for a single and apparentlydominant H2-K b -binding peptide epitope derived fromTRP2 are able to destroy melanocytes in the epidermallayers of the hair follicle. Presumably, CD4 helper T cellsrecognizing the immunogenic marker protein EGFP providelinked help for the induction of TRP2 aa180–188 -specificCD8 þ  cytotoxic T cells. To support this hypothesis, we Figure1 Expression plasmids and recombinant adenoviruses expressingC-terminal fusion proteins between enhanced green fluorescentprotein (EGFP) and defined amino acid sequences of murinetyrosine-related protein 2 (TRP2).  (   A  ) The construction schemes of the expression plasmids pCMV-EGFP.TRP2 aa30–519 , pCMV-EGFP.mTR-P2 aa30–188 , pCMV-EGFP.mTRP2 aa30–179 , and pCMV-EGFP.mTRP2 aa180–188  used in this study are depicted. (  B  ) Additionally, recombinantadenoviruses were generated expressing these fusion proteins andtransgene expression verified by probing lysates of infected 293 cells inwestern blots with EGFP-specific antibodies. TOLERANCE AND IMMUNITY TO MELANOCYTIC SELF-ANTIGENS  145 124:1 JANUARY 2005  genetically immunized groups of CD4-deficient C57BL/6 micewith the expression plasmids pCMV-EGFP.mTRP2 aa180–188 or pCMV-EGFP. None of the 8 CD4-deficient mice investi-gated in two independent experiments developed vitiligo-like coat color changes, indicating the need for CD4 þ  Tcellhelp during the induction phase of the immune response.Furthermore, depletion of CD4 þ  T cells during the primingphase completely prevented the induction of TRP2 aa180–188 -specific CD8 þ  Tcells  in vivo  (data not shown). Influence of a competitively H2-K b -binding epitope inthe helper determinant  It is conceivable that competitivelyH2-K b -binding epitopes in the helper determinant may in-fluence the immunogenicity of the weakly immunogenicself-epitope derived from TRP2. Therefore, we constructedplasmid DNA encoding for the TRP2 aa180–188  peptide at-tached in frame to the C-terminus of the immunogenicmarker protein  b -galactosidase using PCR techniques andinserted this sequence into the CMV-driven expressionplasmid pAdlox as described above.  Escherichia coli   b -ga-lactosidase contains the strong H2-K b -binding peptide epi-tope  b gal aa497–504 . Expression of   b -galactosidase by pCMV- b gal.TRP2 aa180–188  was confirmed  in vitro  by X-gal stainingof transiently transfected 293 cells. Groups of 6 C57BL/6mice were shaved on the abdomen and bombardedwith the expression plasmids pCMV- b gal.TRP2 aa180–188  orpCMV- b gal as a control using the gene gun on a weeklybasis for 5 wk. Again, two mice of each group were sac-rificed 1 wk after the third immunization to analyze inductionof antigen-specific CTL  in vivo  using the IFN g -ELISPOTtechnique. Mice immunized with pCMV- b gal.TRP2 aa180–188 showed reactivity for both the TRP2 aa180–188  and the b gal aa497–504  peptide (Fig 3  A  ). The remaining mice wereagain monitored for coat color changes. As expected, allmice immunized with plasmid DNA expressing the fusionprotein  b gal.TRP2 aa180–188  developed vitiligo-like fur depig-mentation (Fig 3 B  ). This result provides some experimentalevidence that a strong competitively H2-K b -binding epitopein an immunogenic protein such as  b -galactosidase doesnot interfere with the ability to stimulate CD8 þ  T cells in vivo  specific for the attached TRP2 aa180–188  peptide andprecipitate autoimmune vitiligo. Thus, any foreign proteinthat accidentally contains a major histocompatibility com-plex (MHC) class I peptide sequence with similarity to amelanocytic self-antigen and is presented to the immunesystem in an immunogenic way may stimulate cross-reac-tive cytotoxic T cells that are potentially able to destroymelanocytes in the skin. Local inflammation in the skin is required for auto-immune destruction of melanocytes in the effector phase  We previously observed that the injection of recom-binant adenoviruses encoding for the fusion proteinEGFP.TRP2 aa30–519  only very rarely led to vitiligo-like furdepigmentation despite strong stimulation of TRP2 aa180–188 peptide-reactive CD8 þ  T cells  in vivo , which were associ-ated with protective immunity against experimentally in-duced melanoma metastases in the lungs (Steitz  et al  , 2002;Fig 4  A  ). In subsequent experiments, we combined the in- jection of recombinant adenovirus with gene gun bombard-ment of the skin. Groups of six wild-type mice were injected Figure2 Induction of autoreactive CD8 þ  T cells specific for the H2-K  b -binding peptide SVYDFFVWL corresponding to aa180–188 oftyrosine-related protein 2 (TRP2) using the gene gun leads to au-toimmune destruction of melanocytes resulting in vitiligo-like furdepigmentation.  Groups of C57BL/6 mice were immunized by parti-cle-mediated bombardment of the skin with the indicated plasmidDNA. (   A  ) Splenocytes were harvested after immunization and release of IFN g  in response to the H-2K b -binding TRP2 aa180–188  peptide testedusing ELISPOTassays. Results are expressed as mean number of spotforming cells per 10 6 splenocytes. These data are representativeof three to five independent experiments. (  B  ) Alternatively, micewere followed for the appearance of vitiligo-like fur depigmentation.The cumulative number of mice developing coat color changesas a result of the immunization with the indicated plasmid DNA areshown. (  C  ) Representative pictures of mice immunized as indicated areshown. 146  STEITZ  ET AL  THE JOURNAL OF INVESTIGATIVE DERMATOLOGY  intraperitoneally with 5  10 8 p.f.u. of the recombinantadenoviruses Ad-EGFP.TRP2 aa180–188  or Ad- b gal followedafter 1 and 2 wk with gene gun bombardment of the shavedabdomen with the plasmids pCMV-EGFP.TRP2 aa180–188  orpCMV- b gal. Surprisingly, we observed very rapid appear-ance of coat color changes in mice immunized with theEGFP.TRP2 aa180–188  fusion constructs. Depigmented furcould be detected shortly after the second gene gun bom-bardment (Fig 4 B  ). Interestingly, Induction of CD8 þ  T cellsrecognizing the TRP2 aa180–188  peptide  in vivo  using the re-combinant adenovirus Ad-EGFP.TRP2 aa180–188  and genegun bombardment with the irrelevant expression plasmidpCMV- b gal also efficiently promoted fur depigmentation,indicating that local trauma and the associated inflamma-tory response is sufficient to cause autoimmune destructionof melanocytes in the skin. In subsequent experiments, weverified this hypothesis by experimentally inducing a con-tact allergy against Fluovio-2,6-dinitro-benzene (DNFB) incombination with the injection of recombinant adenovirus.Groups of mice were sensitized to DNFB 1 wk before theinjection with Ad-EGFP.TRP2 aa180–188  or Ad- b gal. One weeklater, mice were again treated with DNFB on the ears andthe abdomen to elicit the effector phase of contact allergy. Again, depigmentation of fur could be detected within 2 wkin areas of strong inflammation in the skin (Fig 4 C   ). Discussion The involvement of potentially autoreactive antibodies andcytotoxic T lymphocytes in the pathophysiology of vitiligo isnot completely understood. Recently, the application of  Figure3 The presence of a strong competitively H2-K  b -binding epitope inthe fusion protein between tyrosine-related protein 2 (TRP2) and  Escherichia coli   b -galactosidase did not impair the ability to stim-ulate TRP2-specific CD8 þ  T cells and induce vitiligo.  Groups of C57BL/6 mice were immunized by particle-mediated bombardment of the skin with the indicated plasmid DNA. (   A  ) Splenocytes were har-vested after immunization and release of IFN g  in response to the H-2K b -binding TRP2 aa180–188  peptide tested using ELISPOT assays. Re-sults are expressed as mean number of spot forming cells per 10 6 splenocytes. These data are representative of three to five independentexperiments. (  B  ) Alternatively, mice were followed for the appearanceof vitiligo-like fur depigmentation. The cumulative number of mice de-veloping coat color changes as a result of the immunization with theindicated plasmid DNA are shown. Figure4 Local inflammation in the skin is required for autoimmune de-struction of melanocytes by autoreactive CD8 þ  Tcells specific forthe tyrosine-related protein 2 (TRP2) aa180–188  peptide.  Groups of C57BL/6 mice were treated as indicated and followed for the appear-ance of vitiligo-like fur depigmentation. (   A  ) The cumulative number of mice developing vitiligo-like fur depigmentation in response to intra-peritoneal injection with the indicated recombinant adenoviruses areshown. (  B  ) The cumulative number of mice developing vitiligo-like furdepigmentation in response to a combined immunization with the in-dicated recombinant adenoviruses followed by particle-mediated bom-bardment of the skin with the indicated plasmid DNA are shown. (  C  ).The cumulative number of mice developing vitiligo-like fur depigmen-tation in response to immunization with recombinant adenovirus com-bined with the experimental induction of contact allergy against DNFBare shown. TOLERANCE AND IMMUNITY TO MELANOCYTIC SELF-ANTIGENS  147 124:1 JANUARY 2005  novel genetic immunization strategies for the induction of antigen-specific immune responses against melanosomalenzymes of the tyrosinase family has provided some insightinto the mechanisms regulating immunity and tolerance tothis category of antigens. Stimulation of antibodies as wellas CD4 þ  helper Tcells specific for the brown locus proteingp75/TRP1 has been associated with vitiligo-like fur depig-mentation in C57BL/6 mice (Bowne  et al  , 1999; Overwijk et al  , 1999). Coat color changes were also observed fol-lowing induction of CD8 þ  cytotoxic Tcells specific for theslaty locus protein TRP2 (Bowne  et al  , 1999; Steitz  et al  ,2000). However, vitiligo was not observed with several im-munization strategies including the use of cultured dendriticcells as biological adjuvant despite strong induction of pro-tective immunity against B16 melanoma cells (Bronte  et al  ,2000; Schreurs  et al  , 2000; Steitz  et al  , 2001).In our experiments, we directly addressed the role of CD8 þ  CTL recognizing melanocytic self-antigens for theinduction of vitiligo. We constructed an expression plasmidand a recombinant adenovirus that only encode the nineamino acids SVYDFFVWL corresponding to the H2-K b -binding peptide epitope derived from aa180–188 of themelanosomal enzyme TRP2 attached to the immunogenicmarker protein EGFP. This avoids the potential induction of CD4 þ  Th cells and antibodies specific for TRP2. Severallines of evidence demonstrate that the  in vivo  stimulation of TRP2 aa180–188 -specific CD8 þ  CTL requires EGFP-specificCD4 þ  T helper cells during the induction phase of the im-mune response. Firstly, immunization of CD4-deficient micedid not lead to vitiligo-like depigmentation. Secondly, injec-tion of recombinant adenovirus encoding autologousmurine TRP2 followed by bombardment of the skin withplasmid DNA encoding autologous murine TRP2 did notstimulate TRP2 aa180–188 -specific CD8 þ  Tcells  in vivo  (Steitz et al  , 2000) and never led to autoimmune vitiligo in any of the mice. In contrast, we consistently observed autoim-mune vitiligo in almost every mouse when we intraperitone-ally injected a recombinant adenovirus encoding fusionproteins between EGFP and fragments of TRP2 containingthe TRP2 aa180–188  epitope and subsequently bombardedthe skin with the gene gun. Thirdly, we could demonstratethat the depletion of CD4 þ  T cells immediately before theinjection of recombinant adenoviruses abrogated  in vivo stimulation of TRP2 aa180–188 -specific CD8 þ  T cells.Since TRP2 aa180–188 -specific CD8 þ  CTL precursors ob-viously escape central deletion they must be regulated inthe peripheral immune organs. One possibility is that theysimply ignore their antigen in the skin under normal circum-stances. This has been directly demonstrated in micetransgenically expressing a TCR derived from CD8 þ  CTLrecognizing an altered peptide ligand to aa25–33 of the sil-ver locus protein pmel17/gp100 (Overwijk  et al  , 2003). It isalso conceivable, however, that TRP2 aa180–188 -specific CTLare actively controlled by regulatory Tcells. Recently, it hasbeen shown that such regulatory cells may be stimulated byimmature dendritic cells (Hawiger  et al  , 2001). Indeed, im-mature Langerhans cells from the epidermis constantly car-ry melanosomal proteins to the lymph node (Stoitzner  et al  ,2002). Alternatively, tolerance mechanisms may also be ac-quired during the neonatal period where CD8 þ  Tcells havebeen demonstrated to access the epidermis and becomefunctionally tolerant to peripherally expressed self-antigens(Alferink  et al  , 1998). To overcome peripheral tolerance,naı ¨ ve TRP2 aa180–188 -specific CTL need to be stimulated byactivated antigen-presenting dendritic cells. Interactionswith CD4 þ  Th cells mediated by additional signals such asCD40–CD40L signaling leading to full maturation of dendri-tic cells subsequently control the expansion and the effectorfunction of TRP2 aa180–188 -specific CTL.Similar to other investigators, we found that effective in-duction of TRP2 aa180–188 -specific CD8 þ  CTL  in vivo  is notnecessarily associated with vitiligo-like fur depigmentation.Rather, autoimmune destruction of melanocytes appearedto depend on the immunization strategy. Bombardmentof the skin with the expression plasmid encodingEGFP.TRP2 aa180–188  always led to vitiligo, whereas miceimmunized by intraperitoneal injection with the correspond-ing recombinant adenovirus only rarely developed coat col-or changes. Subsequent experiments combining both genetransfer techniques revealed that autoimmune destructionof melanocytes by activated TRP2 aa180–188 -specific CD8 þ CTL largely depended on the inflammatory stimulus in theskin provided by the particle bombardment. Lane  et al  (2004) recently also reported that vaccination-induced au-toimmune vitiligo is initiated by some form of trauma in theskin. In contrast to our experiments, however, they immu-nize with full-length human TRP2 protein and therefore can-not exclude responses by CD4 þ  Th cells and antibodies.It is currently not exactly known how inflammation andtrauma in the skin promote autoimmune destruction of melanocytes by vaccine-induced TRP2 aa180–188 -specificCD8 þ  CTL. We hypothesize that the production of pro-inflammatory cytokines and chemokines by activatedkeratinocytes following local trauma or inflammation upreg-ulates adhesion molecules on capillary venules, thereby fa-cilitating lymphocyte homing to the skin and providingaccess to antigen-expressing melanocytes in the hair folli-cles. The inflammatory response might also expose me-lanocytes to cytotoxic destruction by upregulating their MHCexpression, which is normally low to absent. Thus, activationof self-reactive T cells can potentially cause autoimmunity if there is a subsequent inflammatory event in the target tissue.This issue is of great importance for the experimental devel-opment of melanoma vaccines, since it implies that me-lanoma cells may also be completely ignored by activatedpigment cell-specific CD8 þ  CTL unless an inflammatorymicroenvironment is established in the tumor tissue.Our results suggest that immunity and tolerance of TRP2 aa180–188 -specific CD8 þ  CTL in mice are regulated intwo steps. In a first general step, stimulation and expansionof melanocyte-specific CD8 þ  CTL in secondary lymphoidtissue are controlled by CD4 þ  Th cells and dendritic cells.In a second tissue-specific step, an inflammatory stimulus isrequired to cause overt autoimmune destruction of me-lanocytes in the skin. A similar observation was reported inan experimental model of transplant tolerance where localinflammation also controlled the rejection of skin grafts car-rying a defined MHC class I alloantigen recognized bytransgenic CD8 þ  CTL (Limmer  et al  , 1998). We envisionthe following possible pathophysiologic scenario for thedevelopment of vitiligo: an infectious pathogen happensto express a protein containing an MHC class I-binding 148  STEITZ  ET AL  THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

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