title: The CD28/CTLA-4-B7 signaling pathway is involved in both allergic sensitization and tolerance induction to orally administered peanut proteins.
abstract: Dendritic cells are believed to play an essential role in regulating the balance between immunogenic and tolerogenic responses to mucosal Ags by controlling T cell differentiation and activation via costimulatory and coinhibitory signals. The CD28/CTLA-4-CD80/CD86 signaling pathway appears to be one of the most important regulators of T cell responses but its exact role in responses to orally administered proteins remains to be elucidated. In the present study, the involvement of the CD28/CTLA-4-CD80/CD86 costimulatory pathway in the induction of allergic sensitization and oral tolerance to peanut proteins was investigated. In both an established C3H/HeOuJ mouse model of peanut hypersensitivity and an oral tolerance model to peanut, CD28/CTLA-4-CD80/CD86 interactions were blocked using the fusion protein CTLA-4Ig. To examine the relative contribution of CD80- and CD86-mediated costimulation in these models, anti-CD80 and anti-CD86 blocking Abs were used. In the hypersensitivity model, CTLA-4Ig treatment prevented the development of peanut extract-induced cytokine responses, peanut extract-specific IgG1, IgG2a, and IgE production and peanut extract-induced challenge responses. Blocking of CD80 reduced, whereas anti-CD86 treatment completely inhibited, the induction of peanut extract-specific IgE. Normal tolerance induction to peanut extract was found following CTLA-4Ig, anti-CD86, or anti-CD80 plus anti-CD86 treatment, whereas blockade of CD80 impaired the induction of oral tolerance. We show that CD28/CTLA-4-CD80/CD86 signaling is essential for the development of allergic responses to peanut and that CD86 interaction is most important in inducing peanut extract-specific IgE responses. Additionally, our data suggest that CD80 but not CD86 interaction with CTLA-4 is crucial for the induction of low dose tolerance to peanut.
authors.affiliation: Utrecht University, Institute for Risk Assessment Sciences, Department of Immunotoxicology, Utrecht, The Netherlands. F.van.Wijk@umcutrecht.nl
authors.forename: Femke
authors.initials: F
authors.lastname: van Wijk
authors.forename: Stefan
authors.initials: S
authors.lastname: Nierkens
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jong
authors.forename: Ellen J M
authors.initials: EJ
authors.lastname: Wehrens
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Peter
authors.initials: P
authors.lastname: van Kooten
authors.forename: Léon M J
authors.initials: LM
authors.lastname: Knippels
authors.forename: Raymond
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000069594:Abatacept; D000284:Administration, Oral; D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D010367:Arachis / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005512:Food Hypersensitivity / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates / Q000008:administration & dosage; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D008024:Ligands; D051379:Mice; D010936:Plant Extracts / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D010940:Plant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000485:Allergens; D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008024:Ligands; D010936:Plant Extracts; D010940:Plant Proteins; D007073:Immunoglobulin E; D000069594:Abatacept