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.

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Presentation transcript:

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 Julia Steitz, Jürgen Brück, Julia Lenz, Steffi Büchs, Thomas Tüting Journal of Investigative Dermatology Volume 124, Issue 1, Pages 144-150 (January 2005) DOI: 10.1111/j.0022-202X.2004.23538.x Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Expression plasmids and recombinant adenoviruses expressing C-terminal fusion proteins between enhanced green fluorescent protein (EGFP) and defined amino acid sequences of murine tyrosine-related protein 2 (TRP2). (A) The construction schemes of the expression plasmids pCMV-EGFP.TRP2aa30–519, pCMV-EGFP.mTRP2aa30–188, pCMV-EGFP.mTRP2aa30–179, and pCMV-EGFP.mTRP2aa180–188 used in this study are depicted. (B) Additionally, recombinant adenoviruses were generated expressing these fusion proteins and transgene expression verified by probing lysates of infected 293 cells in western blots with EGFP-specific antibodies. Journal of Investigative Dermatology 2005 124, 144-150DOI: (10.1111/j.0022-202X.2004.23538.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Induction of autoreactive CD8+ T cells specific for the H2-Kb-binding peptide SVYDFFVWL corresponding to aa180–188 of tyrosine-related protein 2 (TRP2) using the gene gun leads to autoimmune destruction of melanocytes resulting in vitiligo-like fur depigmentation. Groups of C57BL/6 mice were immunized by particle-mediated bombardment of the skin with the indicated plasmid DNA. (A) Splenocytes were harvested after immunization and release of IFNγ in response to the H-2Kb-binding TRP2aa180–188 peptide tested using ELISPOT assays. Results are expressed as mean number of spot forming cells per 106 splenocytes. These data are representative of three to five independent experiments. (B) Alternatively, mice were followed for the appearance of vitiligo-like fur depigmentation. The cumulative number of mice developing coat color changes as a result of the immunization with the indicated plasmid DNA are shown. (C) Representative pictures of mice immunized as indicated are shown. Journal of Investigative Dermatology 2005 124, 144-150DOI: (10.1111/j.0022-202X.2004.23538.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 The presence of a strong competitively H2-Kb-binding epitope in the fusion protein between tyrosine-related protein 2 (TRP2) and Escherichia coliβ-galactosidase did not impair the ability to stimulate TRP2-specific CD8+ 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 harvested after immunization and release of IFNγ in response to the H-2Kb-binding TRP2aa180–188 peptide tested using ELISPOT assays. Results are expressed as mean number of spot forming cells per 106 splenocytes. These data are representative of three to five independent experiments. (B) Alternatively, mice were followed for the appearance of vitiligo-like fur depigmentation. The cumulative number of mice developing coat color changes as a result of the immunization with the indicated plasmid DNA are shown. Journal of Investigative Dermatology 2005 124, 144-150DOI: (10.1111/j.0022-202X.2004.23538.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Local inflammation in the skin is required for autoimmune destruction of melanocytes by autoreactive CD8+ T cells specific for the tyrosine-related protein 2 (TRP2)aa180–188 peptide. Groups of C57BL/6 mice were treated as indicated and followed for the appearance of vitiligo-like fur depigmentation. (A) The cumulative number of mice developing vitiligo-like fur depigmentation in response to intraperitoneal injection with the indicated recombinant adenoviruses are shown. (B) The cumulative number of mice developing vitiligo-like fur depigmentation in response to a combined immunization with the indicated recombinant adenoviruses followed by particle-mediated bombardment of the skin with the indicated plasmid DNA are shown. (C). The cumulative number of mice developing vitiligo-like fur depigmentation in response to immunization with recombinant adenovirus combined with the experimental induction of contact allergy against DNFB are shown. Journal of Investigative Dermatology 2005 124, 144-150DOI: (10.1111/j.0022-202X.2004.23538.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions