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Desmoglein 3–specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice
Hayato Takahashi, … , Shigeo Koyasu, Masayuki Amagai
Hayato Takahashi, … , Shigeo Koyasu, Masayuki Amagai
Published August 8, 2011
Citation Information: J Clin Invest. 2011;121(9):3677-3688. https://doi.org/10.1172/JCI57379.
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Research Article Dermatology

Desmoglein 3–specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice

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Abstract

Pemphigus vulgaris (PV) is a severe autoimmune disease involving blistering of the skin and mucous membranes. It is caused by autoantibodies against desmoglein 3 (Dsg3), an adhesion molecule critical for maintaining epithelial integrity in the skin, oral mucosa, and esophagus. Knowing the antigen targeted by the autoantibodies renders PV a valuable model of autoimmunity. Recently, a role for Dsg3-specific CD4+ T helper cells in autoantibody production was demonstrated in a mouse model of PV, but whether these cells exert cytotoxicity in the tissues is unclear. Here, we analyzed 3 Dsg3-specific TCRs using transgenic mice and retrovirus induction. Dsg3-specific transgenic (Dsg3H1) T cells underwent deletion in the presence of Dsg3 in vivo. Dsg3H1 T cells that developed in the absence of Dsg3 elicited a severe pemphigus-like phenotype when cotransferred into immunodeficient mice with B cells from Dsg3–/– mice. Strikingly, in addition to humoral responses, T cell infiltration of Dsg3-expressing tissues led to interface dermatitis, a distinct form of T cell–mediated autoimmunity that causes keratinocyte apoptosis and is seen in various inflammatory/autoimmune skin diseases, including paraneoplastic pemphigus. The use of retrovirally generated Dsg3-specific T cells revealed that interface dermatitis occurred in an IFN-γ– and TCR avidity–dependent manner. This model of autoimmunity demonstrates that T cells specific for a physiological skin-associated autoantigen are capable of inducing interface dermatitis and should provide a valuable tool for further exploring the immunopathophysiology of T cell–mediated skin diseases.

Authors

Hayato Takahashi, Michiyoshi Kouno, Keisuke Nagao, Naoko Wada, Tsuyoshi Hata, Shuhei Nishimoto, Yoichiro Iwakura, Akihiko Yoshimura, Taketo Yamada, Masataka Kuwana, Hideki Fujii, Shigeo Koyasu, Masayuki Amagai

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Figure 1

Identification of epitope peptides for 3 Dsg3-specific TCRs and a comparison of the differences in their avidities.

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Identification of epitope peptides for 3 Dsg3-specific TCRs and a compar...
(A) TCR-deficient T cell hybridoma was stably transfected by Dsg3H TCR-α and -β chain genes. Successful coexpression of TCR-β chain and CD3 molecules was subsequently detected by flow cytometry. (B) After the Dsg3H, Dsg3L, or Dsg3M hybridoma cell line was cultured with each Dsg3 peptide and irradiated splenocytes or stimulated by anti-CD3 Ab, IL-2 in the supernatant was quantified by ELISA. (C) The Dsg3H-transfectant was stimulated with peptide Dsg3(aa 301–315) in the presence or absence of anti-I-Ab Ab. Then, IL-2 was quantified by ELISA. (D) Dsg3H (line), Dsg3M (thick dotted line), and Dsg3L (fine dotted line) hybridoma cell lines were cultured with various concentrations of the corresponding peptide and irradiated splenocytes and the supernatant was subjected to IL-2 ELISA. Similar results were obtained in 2 separate experiments.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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