Colm B Collins1,2,3, Pamela R Puthoor1,2,4, Tom T Nguyen1,2,3, Derek Strassheim5, Paul Jedlicka6, Jacob E Friedman2, Edwin F de Zoeten1,2,3,4. 1. Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, USA. 2. Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA. 3. Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA. 4. Pediatric Inflammatory Bowel Disease Center, Children's Hospital Colorado, Aurora, CO, USA. 5. Department of Medicine, University of Colorado, Aurora, CO, USA. 6. Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
Abstract
BACKGROUND AND AIMS: Inflammatory Bowel Diseases [IBDs] are chronic intestinal inflammatory conditions in part mediated by CD4+ T cells. Anti-inflammatory Foxp3+ regulatory T cells [Tregs] maintain immune homeostasis and protect against IBD development via multiple mechanisms, including cytokine secretion and cell-cell interaction. CCAAT enhancer binding protein-beta [C/EBPβ] is a stress-responsive transcription factor linked with IBD susceptibility. Whole-body C/EBPβ deficiency induces CD4+ T cell-predominant hyperproliferation, and we hypothesize that this may be due to impaired Treg function. METHODS: We used the C/EBPβ-/- mice in the CD45RBHigh adoptive transfer model, to assess C/EBPβ-/- CD4+ T cells for their colitiogenic potential, and C/EBPβ-/- CD4+ Foxp3+ Tregs for their ability to inhibit colitis. We assessed Tregs from the C/EBPβ-/- mice for expression of Treg functional genes and proteins. RESULTS: Naïve C/EBPβ-/- CD4+ T cells are more colitogenic in vivo. The exacerbated colitis does not appear to reflect impaired Treg development, however, as C/EBPβ-/- mice displayed more, rather than fewer intestinal CD4+Foxp3+ Tregs in vivo. Instead, this reflects impaired Treg function as seen by the reduced capacity to suppress T cell proliferation in vitro, along with decreased secretion of the anti-inflammatory cytokine IL-10. These findings were corroborated in vivo by additional adoptive co-transfer studies in which wildtype Tregs prevented colitis but C/EBPβ-/- Tregs did not. CONCLUSION: C/EBPβ deficiency impairs Treg function and potentiates T cell-mediated colitis. A clearer understanding of the function of this transcription factor may provide a novel therapeutic strategy for IBD.
BACKGROUND AND AIMS: Inflammatory Bowel Diseases [IBDs] are chronic intestinal inflammatory conditions in part mediated by CD4+ T cells. Anti-inflammatory Foxp3+ regulatory T cells [Tregs] maintain immune homeostasis and protect against IBD development via multiple mechanisms, including cytokine secretion and cell-cell interaction. CCAAT enhancer binding protein-beta [C/EBPβ] is a stress-responsive transcription factor linked with IBD susceptibility. Whole-body C/EBPβ deficiency induces CD4+ T cell-predominant hyperproliferation, and we hypothesize that this may be due to impaired Treg function. METHODS: We used the C/EBPβ-/- mice in the CD45RBHigh adoptive transfer model, to assess C/EBPβ-/- CD4+ T cells for their colitiogenic potential, and C/EBPβ-/- CD4+ Foxp3+ Tregs for their ability to inhibit colitis. We assessed Tregs from the C/EBPβ-/- mice for expression of Treg functional genes and proteins. RESULTS: Naïve C/EBPβ-/- CD4+ T cells are more colitogenic in vivo. The exacerbated colitis does not appear to reflect impaired Treg development, however, as C/EBPβ-/- mice displayed more, rather than fewer intestinal CD4+Foxp3+ Tregs in vivo. Instead, this reflects impaired Treg function as seen by the reduced capacity to suppress T cell proliferation in vitro, along with decreased secretion of the anti-inflammatory cytokine IL-10. These findings were corroborated in vivo by additional adoptive co-transfer studies in which wildtype Tregs prevented colitis but C/EBPβ-/- Tregs did not. CONCLUSION: C/EBPβ deficiency impairs Treg function and potentiates T cell-mediated colitis. A clearer understanding of the function of this transcription factor may provide a novel therapeutic strategy for IBD.
Authors: B Singh; S Read; C Asseman; V Malmström; C Mottet; L A Stephens; R Stepankova; H Tlaskalova; F Powrie Journal: Immunol Rev Date: 2001-08 Impact factor: 12.988
Authors: Duke Geem; Oscar Medina-Contreras; Michelle McBride; Rodney D Newberry; Pandelakis A Koni; Timothy L Denning Journal: J Immunol Date: 2014-06-04 Impact factor: 5.422