title: Antigen-presenting cell production of IL-10 inhibits T-helper 1 and 17 cell responses and suppresses colitis in mice.
abstract: OBJECTIVE
  Mice that are deficient in interleukin (IL)-10 develop colitis, mediated by T-helper (Th)1 and Th17 cells, and IL-10-producing regulatory T (Treg) cells suppress colitis, implicating IL-10 in maintaining mucosal homeostasis. We assessed the relative importance of immunoregulatory IL-10 derived from T cells or from antigen presenting cells (APCs) in development of intestinal inflammation.
  
  
  METHODS
  CD4(+) cells from germ-free (GF) or specific pathogen-free (SPF) IL-10(-/-) or wild-type mice were injected into IL-10(-/-), Rag2(-/-) mice or Rag2(-/-) mice that express IL-10. After 6-8 weeks, we evaluated inflammation, spontaneous secretion of cytokines from colonic tissue, and mRNA levels of the transcription factor T-bet and the immunoregulatory cytokine transforming growth factor (TGF)-β. CD4(+) T cells were co-cultured with bacterial lysate-pulsed APCs and assayed for cytokine production, FoxP3 expression, and TGF-β-mediated Smad signaling.
  
  
  RESULTS
  CD4(+) cells from GF or SPF IL-10(-/-) or wild-type mice induced more severe colitis and higher levels of inflammatory cytokines in IL-10(-/-), Rag2(-/-) mice than in IL-10-replete, Rag2(-/-) mice. Co-cultures of IL-10(-/-) or wild-type CD4(+) T cells plus bacterial lysate-pulsed APCs from IL-10(-/-) mice contained more interferon (IFN)-γ, IL-12/23p40, and IL-17 than co-cultures of the same T cells plus APCs from wild-type mice. CD11b(+) APCs were required for these effects. Blocking IL-10 receptors increased production of IFN-γ and IL-12/23p40 whereas exogenous IL-10 suppressed these cytokines. IL-10-producing APCs induced TGF-β-mediated, retinoic acid-dependent, differentiation of FoxP3(+) Treg cells, whereas blocking the retinoic acid receptor, in vitro and in vivo, reduced proportions of FoxP3(+) Treg cells.
  
  
  CONCLUSIONS
  IL-10 produced by APCs regulates homeostatic T-cell responses to commensal bacteria.
authors.affiliation: Institute of Zoonesis, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Susan L
authors.initials: SL
authors.lastname: Tonkonogy
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology*; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005856:Germ-Free Life; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins; D020825:T-Box Domain Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014212:Tretinoin / Q000502:physiology; D000098815:T-bet Transcription Factor
chemical_list: D000942:Antigens, Bacterial; D039481:CD11b Antigen; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D051785:Smad Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D014212:Tretinoin; D007371:Interferon-gamma