title: 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.affiliation: Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Takahashi
authors.forename: Michiyoshi
authors.initials: M
authors.lastname: Kouno
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagao
authors.forename: Naoko
authors.initials: N
authors.lastname: Wada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hata
authors.forename: Shuhei
authors.initials: S
authors.lastname: Nishimoto
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Taketo
authors.initials: T
authors.lastname: Yamada
authors.forename: Masataka
authors.initials: M
authors.lastname: Kuwana
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D003872:Dermatitis / Q000276:immunology* / Q000473:pathology; D051184:Desmoglein 3 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010392:Pemphigus / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D051184:Desmoglein 3; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma