title: Cutting edge: depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice.
abstract: We have recently described two independent mouse models in which the administration of diphtheria toxin (DT) leads to specific depletion of regulatory T cells (Tregs) due to expression of DT receptor-enhanced GFP under the control of the Foxp3 promoter. Both mouse models develop severe autoimmune disorders when Foxp3(+) Tregs are depleted. Those findings were challenged in a recent study published in this journal suggesting the expression of Foxp3 in epithelial cells as the cause for disease development. By using genetic, cellular, and immunohistochemical approaches, we do not find evidence for Foxp3-expression in nonhematopoietic cells. DT injection does not lead to a loss of epithelial integrity in our Foxp3-DTR models. Instead, Foxp3 expression is Treg-specific and ablation of Foxp3(+) Tregs leads to the induction of fatal autoimmune disorders. Autoimmunity can be reversed by the adoptive transfer of Tregs into depleted hosts, and the transfer of Foxp3-deficient bone marrow into T cell-deficient irradiated recipients leads to full-blown disease development.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jeong
authors.initials: J
authors.lastname: Kim
authors.forename: Katharina
authors.initials: K
authors.lastname: Lahl
authors.forename: Shohei
authors.initials: S
authors.lastname: Hori
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chaudhry
authors.forename: Paul
authors.initials: P
authors.lastname: deRoos
authors.forename: Alexander
authors.initials: A
authors.lastname: Rudensky
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D018390:Gene Targeting; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011467:Prostate / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse