title: An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes.
abstract: Maintenance of lymphoid homeostasis in a number of immunological and inflammatory contexts is served by a variety of regulatory T (Treg) cell subtypes and depends on interaction of the transcription factor FoxP3 with specific transcriptional cofactors. We report that a commonly used insertional mutant of FoxP3 (GFP-Foxp3) modified its molecular interactions, blocking HIF-1α but increasing IRF4 interactions. The transcriptional profile of these Treg cells was subtly altered, with an overrepresentation of IRF4-dependent transcripts. In keeping with IRF4-dependent function of Treg cells to preferentially suppress T cell help to B cells and Th2 and Th17 cell-type differentiation, GFP-FoxP3 mice showed a divergent susceptibility to autoimmune disease: protection against antibody-mediated arthritis in the K/BxN model, but greater susceptibility to diabetes on the NOD background. Thus, specific subfunctions of Treg cells and the immune diseases they regulate can be influenced by FoxP3's molecular interactions, which result in divergent immunoregulation.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Darce
authors.forename: Dipayan
authors.initials: D
authors.lastname: Rudra
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Junko
authors.initials: J
authors.lastname: Nishio
authors.forename: Daniela
authors.initials: D
authors.lastname: Cipolletta
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009154:Mutation; D054730:Protein Interaction Domains and Motifs / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
chemical_list: D051858:Forkhead Transcription Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050835:Interferon Regulatory Factors; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C498833:Foxp3 protein, mouse; C497443:Hif1a protein, mouse