title: Induction of autoimmune thyroiditis by depletion of CD4+CD25+ regulatory T cells in thyroiditis-resistant IL-17, but not interferon-gamma receptor, knockout nonobese diabetic-H2h4 mice.
abstract: Iodine-induced experimental autoimmune thyroiditis in the nonobese diabetic (NOD)-H2h4 mouse is a prototype of animal models of Hashimoto's thyroiditis in humans. Recent studies have shown the resistance to thyroiditis of NOD-H2h4 mice genetically deficient for either IL-17 or interferon (IFN)-γ, implicating both of T helper type 1 (Th1) and Th17 immune responses in disease pathogenesis. However, we hypothesized that robust induction of a single arm of effector T cells (either Th1 or Th17) might be sufficient for inducing thyroiditis in NOD-H2h4 mice. To address this hypothesis, enhanced immune responses consisting of either Th1 or Th17 were induced by anti-CD25 antibody-mediated depletion of regulatory T cells (Treg) in thyroiditis-resistant IL-17 knockout (KO) or IFN-γ receptor (IFN-γR) KO, respectively, NOD-H2h4 mice. Depletion of Treg in IL-17 KO mice (i.e. Th1 enhancement) elicited antithyroglobulin autoantibodies and thyroiditis. Immunohistochemical analysis of the thyroid glands revealed the similar intrathyroidal lymphocyte infiltration patterns, with CD4+ T and CD19+ B cells being dominant between the wild-type and Treg-depleted IL-17 KO mice. In contrast, Treg-depleted IFN-γR KO mice remained thyroiditis resistant. Intracellular cytokine staining assays showed differentiation of Th1 cells in IL-17 KO mice but not of Th17 cells in IFN-γR KO mice. Our findings demonstrate that a robust Th1 immune response can by itself induce thyroiditis in otherwise thyroiditis-resistant IL-17 KO mice. Thus, unlike Th17 cells in IFN-γR KO mice, Th1 cells enhanced by Treg depletion can be sustained and induce thyroiditis.
authors.affiliation: Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Horie
authors.forename: Norio
authors.initials: N
authors.lastname: Abiru
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagayama
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000096743:Interferon gamma Receptor
chemical_list: D020381:Interleukin-17; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor