title: Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function.
abstract: Mice with a mutation of the zeta-associated protein of 70 kDa gene (skg mutation) are genetically prone to develop autoimmune arthritis, depending on the environment. In a set of mice with the mutation, the amount of zeta-associated protein of 70 kDa protein as well as its tyrosine phosphorylation upon TCR stimulation decreased from +/+, skg/+, skg/skg, to skg/- mice in a stepwise manner. The reduction resulted in graded alterations of thymic positive and negative selection of self-reactive T cells and Foxp3(+) natural regulatory T cells (Tregs) and their respective functions. Consequently, skg/- mice spontaneously developed autoimmune arthritis even in a microbially clean environment, whereas skg/skg mice required stimulation through innate immunity for disease manifestation. After Treg depletion, organ-specific autoimmune diseases, especially autoimmune gastritis, predominantly developed in +/+, at a lesser incidence in skg/+, but not in skg/skg BALB/c mice, which suffered from other autoimmune diseases, especially autoimmune arthritis. In correlation with this change, gastritis-mediating TCR transgenic T cells were positively selected in +/+, less in skg/+, but not in skg/skg BALB/c mice. Similarly, on the genetic background of diabetes-prone NOD mice, diabetes spontaneously developed in +/+, at a lesser incidence in skg/+, but not in skg/skg mice, which instead succumbed to arthritis. Thus, the graded attenuation of TCR signaling alters the repertoire and the function of autoimmune T cells and natural Tregs in a progressive manner. It also changes the dependency of disease development on environmental stimuli. These findings collectively provide a model of how genetic anomaly of T cell signaling contributes to the development of autoimmune disease.
authors.affiliation: Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Shinji
authors.initials: S
authors.lastname: Maeda
authors.forename: Motomu
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Chihiro
authors.initials: C
authors.lastname: Fujimori
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Ito
authors.forename: Shin
authors.initials: S
authors.lastname: Teradaira
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirota
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshitomi
authors.forename: Tomoya
authors.initials: T
authors.lastname: Katakai
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomura
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakaguchi
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D005838:Genotype; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase