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The CD28/CTLA-4-B7 Signaling Pathway Is Involved in Both Allergic Sensitization and Tolerance Induction to Orally Administered Peanut Proteins

Femke van Wijk^1,*,, Stefan Nierkens, Wilco de Jong^*, Ellen J. M. Wehrens^*, Louis Boon, Peter van Kooten^¶, Léon M. J. Knippels and Raymond Pieters^*

^* Utrecht University, Institute for Risk Assessment Sciences, Department of Immunotoxicology, Utrecht, The Netherlands; TNO Quality of Life, Department of Toxicology and Applied Pharmacology, Zeist, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Department of Tumorimmunology, Nijmegen, The Netherlands; Bioceros B.V., Utrecht, The Netherlands; and ^¶ Utrecht University, Department of Infectious Diseases and Immunology, Utrecht, The Netherlands

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Femke van Wijk, Wilhelmina Children’s Hospital, Pediatric Immunology, PO Box 85090, NL 3508 AB Utrecht, The Netherlands. E-mail address: F.vanWijk{at}umcutrecht.nl

² Abbreviations used in this paper: DC, dendritic cell; DIG, digoxigenin; CT, cholera toxin; Treg, regulatory T cell.