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

研究成果: Article査読

50 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)3677-3688
ページ数12
ジャーナルJournal of Clinical Investigation
121
9
DOI
出版ステータスPublished - 2011 9 1

ASJC Scopus subject areas

  • Medicine(all)

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