title: IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease.
abstract: BACKGROUND
  Recent evidence suggests that IL-17 contributes to airway hyperresponsiveness (AHR); however, the mechanisms that suppress the production of this cytokine remain poorly defined.
  
  
  OBJECTIVE
  We sought to identify the regulatory cells and molecules that suppress IL-17-dependent allergic airways disease.
  
  
  METHODS
  Mice were sensitized by means of airway instillations of ovalbumin together with low levels of LPS. Leukocyte recruitment to the lung and AHR were assessed after daily challenges with aerosolized ovalbumin. Flow cytometry, quantitative PCR, and gene-targeted mice were used to identify naturally arising subsets of regulatory T (Treg) cells and their cytokines required for the suppression of established allergic airway disease.
  
  
  RESULTS
  Allergic sensitization through the airway primed both effector and regulatory responses. Effector responses were initially dominant and led to airway inflammation and IL-17-dependent AHR. However, after multiple daily allergen challenges, IL-17 production and AHR decreased, even though pulmonary levels of T(H)17 cells remained high. This loss of AHR was reversible and required the expansion of a Treg cell subset expressing both forkhead box protein 3 and inducible costimulator. These Treg cells also expressed the regulatory cytokines IL-10, TGF-β, and IL-35. Whereas IL-10 and TGF-β were dispensable for suppression of AHR, IL-35 was required.
  
  
  CONCLUSIONS
  IL-35 production by inducible costimulator-positive Treg cells can suppress IL-17 production and thereby reverse established, IL-17-dependent AHR in mice. Targeting this pathway might therefore be of therapeutic value for treating allergic asthma in human subjects.
authors: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors: Gregory S
authors: GS
authors: Whitehead
authors: Rhonda H
authors: RH
authors: Wilson
authors: Keiko
authors: K
authors: Nakano
authors: Lauranell H
authors: LH
authors: Burch
authors: Hideki
authors: H
authors: Nakano
authors: Donald N
authors: DN
authors: Cook
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism*; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000494:pharmacology; D007378:Interleukins / Q000096:biosynthesis*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D020381:Interleukin-17; D007378:Interleukins; C569375:interleukin-35, mouse