title: TGF-β induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentiation.
abstract: Mice deficient in the adaptor Ndfip1 develop inflammation at sites of environmental antigen exposure. We show here that such mice had fewer inducible regulatory T cells (iT(reg) cells). In vitro, Ndfip1-deficient T cells expressed normal amounts of the transcription factor Foxp3 during the first 48 h of iT(reg) cell differentiation; however, this expression was not sustained. Abortive Foxp3 expression was caused by production of interleukin 4 (IL-4) by Ndfip1(-/-) cells. We found that Ndfip1 expression was transiently upregulated during iT(reg) cell differentiation in a manner dependent on transforming growth factor-β (TGF-β). Once expressed, Ndfip1 promoted degradation of the transcription factor JunB mediated by the E3 ubiquitin ligase Itch, thus preventing IL-4 production. On the basis of our data, we propose that TGF-β signaling induces Ndfip1 expression to silence IL-4 production, thus permitting iT(reg) cell differentiation.
authors.affiliation: Cell Pathology Division, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Beal
authors.forename: Natalia
authors.initials: N
authors.lastname: Ramos-Hernández
authors.forename: Chris R
authors.initials: CR
authors.lastname: Riling
authors.forename: Erin A
authors.initials: EA
authors.lastname: Nowelsky
authors.forename: Paula M
authors.initials: PM
authors.lastname: Oliver
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases
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