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

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 3

Tolerized Dsg3H1 T cells induced interface dermatitis, but not PV.

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Tolerized Dsg3H1 T cells induced interface dermatitis, but not PV. (A) T...
(A) The skin phenotype of Rag2–/– mice (n = 3 per group) given CD4+Vβ6+ cells from Dsg3H1 mice or CD4+ T cells from C57BL/6 mice in combination with Dsg3–/– B cells. Erosive and crusted lesion in the perioral region, upper limbs, paws, and tail and hair loss on the chest were evident (upper panels). (B) Pathology of the skin in the recipients given CD4+Vβ6+ cells from Dsg3H1 mice or WT CD4+ T cells. (C) Various Dsg3-expressing tissues in the recipients of CD4+Vβ6+ cells from Dsg3H1 mice were stained with H&E. Blue arrowheads indicate degenerated cells in the epithelium. Yellow arrowheads indicate intraepithelial inflammatory cells. Blue arrows indicate liquefaction degeneration in the basal layer of the lesional epithelium. Yellow arrow indicates a degenerated cell well stained with eosin, a so-called Civatte body. (D) The palate was stained with anti–TCR-β chain (red) and anti-IgG (green) Abs and TOTO3 (blue). Dotted lines indicate the basement membrane zone. (E) A single-cell suspension was prepared from the lesional skin of the recipients given CD4+Vβ6+ cells from Dsg3H1 mice and analyzed by flow cytometry after gating into the CD45+7-AAD– population. Scale bars: 50 μm.