Prevention of toxic epidermal necrolysis by regulatory T cells

Azukizawa, Hiroaki; Sano, Shigetoshi; Kanazawa, Hiroshi; Sumikawa, Yasuyuki; Itami, Satoshi

doi:10.1002/eji.200425773

Cited by 44 publications

(39 citation statements)

References 37 publications

(38 reference statements)

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“…Peptide epitopes were expressed with signal sequences, which bypassed the need for antigen processing and directed the epitope directly to the ER for MHC class I binding. A single study using whole OVA protein under a K5 promoter indicated that OVA-expressing thymic epithelium induced deletion of OVA-specific T cells [8]. In contrast to these studies, our data indicated that a subset of proteins expressed by the epithelium, e.g.…”

Section: Discussioncontrasting

confidence: 91%

“…Consistent with earlier studies in K14E7 mice on F1 mouse backgrounds, the silencing of CD8 T cells in the K14E7.C57 periphery was found to extend to other antigens not encoded by the E7 transgene, suggesting a suppressive immune environment [14]. This contrasts with K5 or K14 OVA-based models, where autoimmune skin disease is observed [8,[22][23][24]. Surprisingly, CD8 T-cell responses to immunization were suppressed in K14E7 mice whereas CD4 T-cell and B-cell responses were not.…”

Section: Discussionsupporting

confidence: 88%

“…Finally, a significant difference between our studies and the earlier work demonstrating thymic tolerance to epithelial peptides is our use of TCR-b transgenic mice, where endogenous TCR alpha chain pairing occurs in these mice with appropriate timing during T-cell development [21]. The early expression of both transgenic TCR alpha and beta proteins specific for OVA [8], 2C ligand or HY male antigen [7] may enable cortical epithelium to mediate deletion or receptor editing due to long periods of TCR-MHC interaction during T-cell development. E7-specific CD8 T cells that emerge from the K14E7 thymus undergo silencing in the periphery.…”

Section: Discussionmentioning

confidence: 95%

“…Evidence for the role of cortical epithelial cells in positive selection comes from studies of MHC expression driven from a keratin 14 (K14) promoter in otherwise MHC-deficient mice [5,6]. In contrast, expression of protein and peptide antigens in K14 1 thymic epithelium results in the deletion of antigen-specific CD8 T cells and the editing of the transgenic TCR [7][8][9]. Consequently, depending on the model, T cells are either positively selected or negatively selected after contact with thymic epithelium.…”

Section: Introductionmentioning

confidence: 99%

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Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

et al. 2009

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The role of thymic versus peripheral epithelium in the regulation of the antigen-specific CD8 T-cell repertoire is still largely unresolved. We generated TCR-b chain transgenic mice in which an increased frequency of peripheral CD8 T cells recognizes an epitope from a viral oncoprotein (HPV16E7) in the context of H-2D b MHC class I. When T cells from these mice developed through the thymus of mice expressing functional E7 protein from a keratin 14 promoter, no major perturbation to transgenic T-cell development in the thymus was observed in these double-transgenic mice. In contrast, peripheral CD8 T-cell responses in the single-transgenic, K14E7 mice, including those unrelated to E7 antigen, are reduced whereas CD4 T-cell responses and antibody production are unchanged in these mice. Peripheral non-responsiveness among CD8 T cells was mediated largely by CD4 1 CD25 1 T cells. This suggested that epithelium expressing HPV16E7 protein inducesTreg that specifically down-regulate CD8 T-cell responses in the periphery. This may have important consequences for the treatment of cervical pre-cancers and provides a model for understanding differential suppression of T and B lymphocyte subsets by Treg.Key words: Skin . Suppression . T cells . Thymus . Transgenic mice IntroductionT-cell development starts in the thymus, where lymphocytes expressing TCR recognize self-peptides bound to MHC class I. Immature T cells are either deleted if the affinity of interaction is high (negative selection) or retained for export to the periphery if the affinity is low (positive selection). Medullary epithelial cells and DC are thought to induce negative selection whereas cortical epithelial cells positively select the T-cell repertoire [1][2][3][4]. Evidence for the role of cortical epithelial cells in positive selection comes from studies of MHC expression driven from a keratin 14 (K14) promoter in otherwise MHC-deficient mice [5,6]. In contrast, expression of protein and peptide antigens in K14 1 thymic epithelium results in the deletion of antigen-specific CD8 T cells and the editing of the transgenic TCR [7][8][9]. Consequently, depending on the model, T cells are either positively selected or negatively selected after contact with thymic epithelium. HPV16E7 is one of the key oncogenes expressed during progression to cervical cancer: the protein is expressed in the epithelial cells of the cervix during human papillomavirus (HPV) infection and subsequent cancer development [10]. Given that mice cannot be naturally infected with HPV, human cervical cancer has been modeled in mice by transgenic expression of HPV16E7 leading to E7 expression in the thymus and peripheral epithelial sites, e.g. skin keratinocytes [11,12]. The first such K14E7 transgenic mice were generated on an FVB mouse 481background that failed to present the dominant CD8 T-cell peptide identified in the C57BL/6 background [12]. Subsequently, K14E7FVB Â C57 F1 mice were generated and shown to have poor CD8 T-cell responses that were attributable to the induction of per...

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Section: Discussioncontrasting

confidence: 91%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

et al. 2009

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“…In this regard, regulatory T (Treg) cells are most likely candidates to search for inadequate down-regulation in severe drug eruptions. Indeed, Azukizawa et al (5) reported that in an animal model of TEN Treg cells can prevent experimentally induced epidermal injury mimicking TEN (6), although the therapeutic effect cannot be observed. Thus, drug-induced immunopathology is likely to be subject to control by Treg cells.…”

mentioning

confidence: 99%

Defective Regulatory T Cells In Patients with Severe Drug Eruptions: Timing of the Dysfunction Is Associated with the Pathological Phenotype and Outcome

Takahashi

Kano

Yamazaki

et al. 2009

The Journal of Immunology

243

203

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Toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS) represent two ends of a spectrum of severe drug eruptions: DIHS is unique in that severe epidermal damage seen in TEN is absent, sequential reactivations of herpesviruses occur, and autoimmunity often ensues. To investigate whether changes in regulatory T (Treg) cell function would contribute to variability in the clinical manifestations, we examined the frequency, phenotype, and function of Treg cells both during the acute stage and again long after clinical resolution of both diseases. Dramatic expansions of functional Treg cells were found in the acute stage of DIHS. In contrast, Treg function was profoundly impaired in TEN, although present in normal frequency. Skin homing addressins were more preferentially expressed on Treg cells in DIHS than in TEN. Indeed, Treg cells were more abundantly present in the skin lesions of DIHS. Surprisingly, Treg cells contracted upon resolution of DIHS became functionally deficient, whereas their functional defects in TEN were restored upon recovery. These findings indicate that a transitory impairment in their function during the acute stage of TEN may be related to severe epidermal damage, while a gradual loss of their function after resolution of DIHS may increase the risk of subsequently developing autoimmune disease.

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Lichen Planus

Mangold

Pittelkow

2017

Clinical and Basic Immunodermatology

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Prevention of toxic epidermal necrolysis by regulatory T cells

Cited by 44 publications

References 37 publications

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

Defective Regulatory T Cells In Patients with Severe Drug Eruptions: Timing of the Dysfunction Is Associated with the Pathological Phenotype and Outcome

Lichen Planus

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Prevention of toxic epidermal necrolysis by regulatory T cells

Cited by 44 publications

References 37 publications

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4+CD25+ T cells

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4+CD25+ T cells

Defective Regulatory T Cells In Patients with Severe Drug Eruptions: Timing of the Dysfunction Is Associated with the Pathological Phenotype and Outcome

Lichen Planus

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Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells