title: Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8.
abstract: OBJECTIVE
  The intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)-β is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3(+) regulatory T cells (Tregs) that suppress immune responses. TGF-β is expressed at high levels in the gastrointestinal tract as a latent complex that must be activated. However, the pathways that control TGF-β activation in the intestine are poorly defined. We investigated the cellular and molecular pathways that control activation of TGF-β and induction of Foxp3(+) Tregs in the intestines of mice to maintain immune homeostasis.
  
  
  METHODS
  Subsets of intestinal dendritic cells (DCs) were examined for their capacity to activate TGF-β and induce Foxp3(+) Tregs in vitro. Mice were fed oral antigen, and induction of Foxp3(+) Tregs was measured.
  
  
  RESULTS
  A tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-β, and induced Foxp3(+) Tregs independently of the vitamin A metabolite retinoic acid. The integrin αvβ8, which activates TGF-β, was significantly up-regulated on CD103(+) intestinal DCs. DCs that lack expression of integrin αvβ8 had reduced ability to activate latent TGF-β and induce Foxp3(+) Tregs in vitro and in vivo.
  
  
  CONCLUSIONS
  CD103(+) intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin αvβ8-mediated activation of TGF-β.
authors: Manchester Immunology Group and Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors: John J
authors: JJ
authors: Worthington
authors: Beata I
authors: BI
authors: Czajkowska
authors: Andrew C
authors: AC
authors: Melton
authors: Mark A
authors: MA
authors: Travis
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007107:Immune System / Q000502:physiology; D066298:In Vitro Techniques; D039001:Integrin alpha Chains / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D007422:Intestines / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D010047:Ovalbumin / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D039001:Integrin alpha Chains; D016023:Integrins; D016212:Transforming Growth Factor beta; C091367:alpha E integrins; C403414:integrin alphavbeta8; D014212:Tretinoin; D010047:Ovalbumin