title: IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor.
abstract: Forkhead box P3 positive (Foxp3(+)) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NFκB (IκB) IκB(NS) drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκB(NS) deficiency leads to a substantial reduction of Foxp3(+) Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-β (TGF-β) treatment in vitro. Moreover, fewer Foxp3(+) Treg cells developed from IκB(NS)-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, IκB(NS) was required for the transition of immature GITR(+)CD25(+)Foxp3(-) thymic Treg cell precursors into Foxp3(+) cells. In contrast to mice lacking c-Rel or Carma1, IκB(NS)-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκB(NS) critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκB(NS) could modulate the Treg cell compartment.
authors.affiliation: Systems-oriented Immunology and Inflammation Research, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schuster
authors.forename: Rainer
authors.initials: R
authors.lastname: Glauben
authors.forename: Carlos
authors.initials: C
authors.lastname: Plaza-Sirvent
authors.forename: Lisa
authors.initials: L
authors.lastname: Schreiber
authors.forename: Michaela
authors.initials: M
authors.lastname: Annemann
authors.forename: Stefan
authors.initials: S
authors.lastname: Floess
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.forename: Linda K
authors.initials: LK
authors.lastname: Clayton
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D020672:I-kappa B Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056747:Immunomodulation; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D051858:Forkhead Transcription Factors; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D052002:NF-kappa B p50 Subunit; D011506:Proteins; D020569:Proto-Oncogene Proteins c-rel; D016212:Transforming Growth Factor beta; C498833:Foxp3 protein, mouse; C454819:Nfkbid protein, mouse