Title
The CD28/CTLA-4-B7 signaling pathway is involved in both allergic sensitization and tolerance induction to orally administered peanut proteins
Author
van Wijk, F.
Nierkens, S.
de Jong, W.
Wehrens, E.J.M.
Boon, L.
van Kooten, P.
Knippels, L.M.J.
Pieters, R.
TNO Kwaliteit van Leven
Publication year
2007
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, CB28/CTLA-4-CB80/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 CB80 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. Copyright © 2007 by The American Association of Immunologists, Inc.
Subject
Nutrition
Toxicology and Applied Pharmacology
Chymase
Cytotoxic T lymphocyte antigen 4
Immunoglobulin G1
Immunoglobulin G2a
Peanut protein
Protein
Mouse
Peanut allergy
Sensitization
Signal transduction
T lymphocyte
T lymphocyte activation
Administration, Oral
Allergens
Animals
Antibodies, Blocking
Antigens, CD
Antigens, CD28
Antigens, CD80
Antigens, Differentiation
Arachis hypogaea
Cells, Cultured
Disease Models, Animal
Food Hypersensitivity
Immune Tolerance
Immunoconjugates
Immunoglobulin E
Ligands
Mice
Plant Extracts
Plant Proteins
Signal Transduction
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http://resolver.tudelft.nl/uuid:4d6e3f33-8608-45e5-b143-1f39ac140e40
TNO identifier
239988
ISSN
0022-1767
Source
Journal of Immunology, 178 (11), 6894-6900
Document type
article