title: Regulatory dendritic cell expression of MHCII and IL-10 are jointly requisite for induction of tolerance in a murine model of OVA-asthma.
abstract: BACKGROUND
  Allergen-presenting dendritic cells differentiated with IL-10 (DC10) reverse the asthma phenotype in mice by converting their Th2 cells to regulatory T cells (Tregs). DC10 express elevated levels of IL-10, but substantially reduced levels of MHCII and costimulatory molecules, so the relationships between these factors with each other and tolerogenicity have not been clearly elucidated.
  
  
  METHODS
  We assessed the roles of these inputs in DC10 reversal of OVA-associated asthma-like disease by treating affected mice with OVA-pulsed DC10 generated from wild-type or IL-10-sufficient MHCII(-/-) or CD80/CD86(-/-) mice, or with MHCII-intact IL-10-silenced DC10.
  
  
  RESULTS
  IL-10 silencing did not discernibly affect the cells' immunobiology (e.g., costimulatory molecules, chemokines), but it eliminated IL-10 secretion and the cell's abilities to induce tolerance, as determined by assessments of airway hyper-responsiveness, eosinophilia, and Th2 responses to recall OVA challenge. MHCII(-/-) DC10 expressed normal levels of IL-10, but, nevertheless, were unable to induce allergen tolerance in asthma phenotype mice, while tolerance induced by CD80/CD86(-/-) DC10 was attenuated but not eliminated. We also assessed the induction of multiple Treg cell markers (e.g., ICOS, PD-1, GITR) on pulmonary CD25(+) Foxp3(+) cells in the treated mice. Wild-type DC10 treatments upregulated expression of each marker, while neither IL-10-silenced nor MHCII(-/-) DC10 did so, and the CD80/86(-/-) DC10 induced an intermediate Treg cell activation phenotype.
  
  
  CONCLUSIONS
  Both IL-10 and MCHII expression by DC10 are requisite, but not sufficient for tolerance induction, suggesting that DC10 and Th2 effector T cells must be brought together in a cognate fashion in order for their IL-10 to induce tolerance.
authors.affiliation: Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.forename: W
authors.initials: W
authors.lastname: Dawicki
authors.forename: M
authors.initials: M
authors.lastname: Lu
authors.forename: A
authors.initials: A
authors.lastname: Nayyar
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J R
authors.initials: JR
authors.lastname: Gordon
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II / Q000235:genetics*; D007108:Immune Tolerance / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000009:adverse effects; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; D010047:Ovalbumin
keywords: CD80/CD86; IL-10; MHCII; asthma; tolerogenic dendritic cells