title: Cell-intrinsic NF-κB activation is critical for the development of natural regulatory T cells in mice.
abstract: BACKGROUND
  Naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells develop in the thymus and represent a mature T cell subpopulation critically involved in maintaining peripheral tolerance. The differentiation of Treg cells in the thymus requires T cell receptor (TCR)/CD28 stimulation along with cytokine-promoted Foxp3 induction. TCR-mediated nuclear factor kappa B (NF-κB) activation seems to be involved in differentiation of Treg cells because deletion of components of the NF-κB signaling pathway, as well as of NF-κB transcription factors, leads to markedly decreased Treg cell numbers in thymus and periphery.
  
  
  RESULTS
  To investigate if Treg cell-intrinsic NF-κB activation is required for thymic development and peripheral homeostasis of Treg cells we used transgenic (Tg) mice with thymocyte-specific expression of a stable IκBα mutant to inhibit NF-κB activation solely within the T cell lineage. Here we show that Treg cell-intrinsic NF-κB activation is important for the generation of cytokine-responsive Foxp3(-) thymic Treg precursors and their further differentiation into mature Treg cells. Treg cell development could neither be completely rescued by the addition of exogenous Interleukin 2 (IL-2) nor by the presence of wild-type derived cells in adoptive transfer experiments. However, peripheral NF-κB activation appears to be required for IL-2 production by conventional T cells, thereby participating in Treg cell homeostasis. Moreover, pharmacological NF-κB inhibition via the IκB kinase β (IKKβ) inhibitor AS602868 led to markedly diminished thymic and peripheral Treg cell frequencies.
  
  
  CONCLUSIONS
  Our results indicate that Treg cell-intrinsic NF-κB activation is essential for thymic Treg cell differentiation, and further suggest pharmacological NF-κB inhibition as a potential therapeutic approach for manipulating this process.
authors.affiliation: Clinical Research Group at Nikolaus Fiebiger Center of Molecular Medicine, Department of Internal Medicine 3, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Gückel
authors.forename: Silke
authors.initials: S
authors.lastname: Frey
authors.forename: Mario M
authors.initials: MM
authors.lastname: Zaiss
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Sankar
authors.initials: S
authors.lastname: Ghosh
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004797:Enzyme-Linked Immunosorbent Assay; D006706:Homeostasis; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology
chemical_list: D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell