Novel system evaluating in vivo pathogenicity of desmoglein 3-reactive T cell clones using murine pemphigus vulgaris.
Autoreactive T cells are thought to be involved in the pathogenesis of autoimmune diseases, but evidence for their direct pathogenicity is almost lacking. Herein we established a unique system for evaluating the in vivo pathogenicity of desmoglein 3 (Dsg3)-reactive T cells at a clonal level in a mouse model for pemphigus vulgaris (PV), an autoimmune blistering disease induced by anti-Dsg3 autoantibodies. Dsg3-reactive CD4(+) T cell lines generated in vitro were adoptively transferred into Rag-2(-/-) mice with primed B cells derived from Dsg3-immunized Dsg3(-/-) mice. Seven of 20 T cell lines induced IgG anti-Dsg3 Ab production and acantholytic blister, a typical disease phenotype, in recipient mice. Comparison of the characteristics between pathogenic and nonpathogenic Dsg3-reactive T cell lines led to the identification of IL-4 and IL-10 as potential factors associated with pathogenicity. Further in vitro analysis showed that IL-4, but not IL-10, promoted IgG anti-Dsg3 Ab production by primed B cells. Additionally, adenoviral expression of soluble IL-4Ralpha in vivo suppressed IgG anti-Dsg3 Ab production and the PV phenotype, indicating a pathogenic role of IL-4. This strategy is useful for evaluating the effector function of autoreactive T cells involved in the pathogenesis of various autoimmune diseases.
Takahashi
Hayato
H
Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
Amagai
Masayuki
M
Nishikawa
Takeji
T
Fujii
Yoshiko
Y
Kawakami
Yutaka
Y
Kuwana
Masataka
M
D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D051184:Desmoglein 3 / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000502:physiology; D015847:Interleukin-4 / Q000276:immunology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010392:Pemphigus / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit
D001323:Autoantibodies; D051184:Desmoglein 3; D007371:Interferon-gamma; D016753:Interleukin-10; D015847:Interleukin-4; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit