title: CD4(+) CD25(+) T regulatory cells do not transfer oral tolerance to peanut allergens in a mouse model of peanut allergy.
abstract: BACKGROUND
  Recent studies have implicated CD4(+) CD25(+) regulatory T cells (nTregs) in the maintenance of tolerance to oral antigens and in the regulation of the food allergic IgE response.
  
  
  OBJECTIVE
  The objective was to assess if nTregs can transfer allergen-specific oral tolerance to naïve, non-TCR transgenic mice and regulate peanut extract (PE)-specific hypersensitivity responses. Additionally, the role of the regulatory cytokines IL-10 and TGF-β in the modulation of peanut-allergic sensitization was studied.
  
  
  METHODS
  CD25-enriched T cells from PE-tolerant mice were adoptively transferred to recipient mice, which were subsequently sensitized to PE. Depletion of CD25(+) cells and neutralization of IL-10 and TGF-β were compared in a CH3/HeOuJ mouse model of peanut-allergic sensitization.
  
  
  RESULTS
  Transfer of CD25(+) Tregs-enriched cell populations did not affect the PE-specific cytokine production or PE-specific antibody levels compared with control mice but interestingly resulted in a decrease of mast cell responsiveness. On the contrary, transfer of CD25(+) Tregs-depleted cells caused an increase in non-specific cytokine production, in the absence of changes in PE-specific responses. TGF-β neutralization resulted even in a larger increase in spontaneous release of all cytokines measured (IL-4, IL-5, IL-10, IL-13, and IFN-γ), but surprisingly also to a higher PE-specific Th2-associated (IL-4, IL-5, IL-13) cytokine production compared with depletion of CD25 cells or neutralization of IL-10. Similarly, depletion of CD25 cells and TGF-β neutralization but not of IL-10 neutralization lead to an increase in PE-specific antibody levels and elevated mast cell degranulation following a PE challenge.
  
  
  CONCLUSIONS
  We conclude that CD4(+) CD25(+) Tregs from non-transgenic-tolerant mice cannot transfer specific oral tolerance of exogenous antigens to naïve mice and are more involved in general immune suppressive mechanisms. However, we found evidence that TGF-β secreting Tregs (Th3) may play an important role.
authors.affiliation: Institute for Risk Assessment Sciences, Immunotoxicology, Utrecht University, Utrecht, The Netherlands. m.marcondesrezende@uu.nl
authors.forename: M
authors.initials: M
authors.lastname: Marcondes Rezende
authors.forename: I
authors.initials: I
authors.lastname: Hassing
authors.forename: M
authors.initials: M
authors.lastname: Bol-Schoenmakers
authors.forename: R
authors.initials: R
authors.lastname: Bleumink
authors.forename: L
authors.initials: L
authors.lastname: Boon
authors.forename: J
authors.initials: J
authors.lastname: van Bilsen
authors.forename: R
authors.initials: R
authors.lastname: Pieters
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D010367:Arachis / Q000276:immunology*; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D021183:Peanut Hypersensitivity / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000485:Allergens; D000906:Antibodies; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit