title: p27(Kip1)  inhibits systemic autoimmunity through the control of Treg cell activity and differentiation.
abstract: OBJECTIVE
  Despite the importance of Treg cells in the maintenance of immunologic tolerance, the mechanisms that control their generation and activity are unknown. Since the cell cycle inhibitor p27(Kip1)  (p27) was involved in T cell anergy, we undertook this study to explore its role in both Treg cell processes.
  
  
  METHODS
  The development of type II collagen-induced arthritis (CIA) and lupus-like abnormalities was compared between transgenic mice overexpressing human Bcl-2 in T cells (BCL2-TgT mice) and nontransgenic mice that were deficient or not deficient in p27. The contribution of Treg cells to disease evolution was also explored. Finally, the in vitro activity of Treg cells and their differentiation from naive CD4+ cells was compared between these strains of mice.
  
  
  RESULTS
  BCL2-TgT mice were protected against CIA by a Treg cell-dependent mechanism. In association with this protection, the overexpression of Bcl-2 in T cells enhanced the differentiation and activity of Treg cells. Both Bcl-2 effects were independent of its antiapoptotic activity but dependent on its capacity to induce the expression of p27 that augmented the strength of transforming growth factor β (TGFβ) signaling in T cells. Accordingly, down-modulation of p27 expression in BCL2-TgT mice promoted CIA. In addition, p27 deficiency in aged C57BL/6 mice reduced the number and activity of Treg cells and induced the development of mild lupus-like abnormalities.
  
  
  CONCLUSIONS
  Our results point to p27 as a critical regulator of Treg cell differentiation and function through the positive modulation of TGFβ signaling strength in T cells.
authors.affiliation: Universidad de Cantabria-IFIMAV, Santander, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Iglesias
authors.forename: Jorge
authors.initials: J
authors.lastname: Postigo
authors.forename: Inés
authors.initials: I
authors.lastname: Santiuste
authors.forename: Jovanna
authors.initials: J
authors.lastname: González
authors.forename: Luis
authors.initials: L
authors.lastname: Buelta
authors.forename: Esther
authors.initials: E
authors.lastname: Tamayo
authors.forename: Jesús
authors.initials: J
authors.lastname: Merino
authors.forename: Ramón
authors.initials: R
authors.lastname: Merino
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27