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

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

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 2

Generation of the Dsg3-specific TCR-transgenic mouse, Dsg3H1 mouse, and Dsg3 reactivity of transgenic T cells.

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Generation of the Dsg3-specific TCR-transgenic mouse, Dsg3H1 mouse, and ...
(A) Thymocytes were stained with anti-CD4 and -CD8 Abs and analyzed by flow cytometry. (B) Single-cell suspensions from the spleen and LNs were stained with anti-CD4 and -Vβ6 Abs and analyzed. (C) Splenocytes from Dsg3H1 mice were cultured with the peptide Dsg3(aa 301–315) or a control peptide. 3H-thymidine incorporation by these splenocytes is shown as the in vitro reactivity against Dsg3 peptide. (D) CFSE-labeled CD4+ T cells from Dsg3H1 mice were transferred into B6 WT mice and Dsg1tg/tgDsg3–/– mice. 3 days later, CFSE dilution was analyzed by flow cytometry after gating CD4+Vβ6+ cells of the spleen, skin-draining LN (sLN), and mesentery LN (mLN) from both recipients. Proportions of dividing cells were shown in each histogram. Similar results were obtained in 2 separate experiments. Data represent mean ± SEM.