title: Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.
abstract: The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3-4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome-transgenic mice termed "depletion of regulatory T cell" (DEREG) mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3+ T reg cells by DT injection. Ablation of Foxp3+ T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3+ T reg cells in immune reactions in vivo.
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, 81675 Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Lahl
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Cathy
authors.initials: C
authors.lastname: Drouin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Freyer
authors.forename: Jon
authors.initials: J
authors.lastname: Arnason
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004167:Diphtheria Toxin / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008232:Lymphoproliferative Disorders / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D017931:DNA Primers; D004167:Diphtheria Toxin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins