An N-terminal mutation of the FoxP3 transcription factor alleviates arthritis but exacerbates diabetes Journal Article

   

Authors:	Darce, J.; Rudra, D.; Li, L.; Nishio, J.; Cipolletta, D.; Rudensky, A. Y.; Mathis, D.; Benoist, C.
Article 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. © 2012 Elsevier Inc.
Keywords:	controlled study; gene mutation; mutation; nonhuman; transcription factor foxp3; forkhead transcription factors; animal cell; mouse; phenotype; animals; mice; gene targeting; protein protein interaction; animal experiment; animal model; cell differentiation; mice, inbred c57bl; immunoregulation; b-lymphocytes; transcription factors; disease model; lymphocyte differentiation; regulatory t lymphocyte; th2 cell; amino terminal sequence; t-lymphocytes, regulatory; arthritis; nucleotide sequence; diabetes mellitus; th17 cell; autoimmune diseases; autoimmune disease; homeostasis; diabetes mellitus, type 1; mice, inbred nod; disease predisposition; nonobese diabetic mouse; hypoxia inducible factor 1alpha; disease exacerbation; protein interaction domains and motifs; lymphocyte function; interferon regulatory factor 4; protein modification; hypoxia-inducible factor 1, alpha subunit; interferon regulatory factors; th2 cells; th17 cells; humoral immune deficiency
Journal Title:	Immunity
Volume:	36
Issue:	5
ISSN:	1074-7613
Publisher:	Cell Press
Date Published:	2012-05-25
Start Page:	731
End Page:	741
Language:	English
DOI:	10.1016/j.immuni.2012.04.007
PROVIDER:	scopus
PUBMED:	22579475
PMCID:	PMC3386606
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84861424521&partnerID=40&md5=344057a70bfd850db88f6c18c6f00674
Notes:	--- - "Export Date: 4 June 2012" - "CODEN: IUNIE" - "Source: Scopus"

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