title: Tolerance to ingested deamidated gliadin in mice is maintained by splenic, type 1 regulatory T cells.
abstract: OBJECTIVE
  Patients with celiac disease have permanent intolerance to gluten. Because of the high frequency of this disorder (approximately 1 in 100 individuals), we investigated whether oral tolerance to gluten differs from that to other food proteins.
  
  
  METHODS
  Using transgenic mice that express human HLA-DQ2 and a gliadin-specific, humanized T-cell receptor, we compared gluten-specific T-cell responses with tolerogenic mucosal T-cell responses to the model food protein ovalbumin.
  
  
  RESULTS
  Consistent with previous findings, the ovalbumin-specific response occurred in the mesenteric lymph nodes and induced Foxp3(+) regulatory T cells. In contrast, ingestion of deamidated gliadin induced T-cell proliferation predominantly in the spleen but little in mesenteric lymph nodes. The gliadin-reactive T cells had an effector-like phenotype and secreted large amounts of interferon gamma but also secreted interleukin-10. Despite their effector-like phenotype, gliadin-reactive T cells had regulatory functions, because transfer of the cells suppressed a gliadin-induced, delayed-type hypersensitivity response.
  
  
  CONCLUSIONS
  Ingestion of deamidated gliadin induces differentiation of tolerogenic, type 1 regulatory T cells in spleens of HLA-DQ2 transgenic mice. These data indicate that under homeostatic conditions, the T-cell response to deamidated gliadin is tolerance, which is not conditioned by the mucosal immune system but instead requires interleukin-10 induction by antigen presentation in the spleen.
authors.affiliation: Department of Pediatrics, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M Fleur
authors.initials: MF
authors.lastname: Du Pré
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kozijn
authors.forename: Lisette A
authors.initials: LA
authors.lastname: van Berkel
authors.forename: Mariëtte N D
authors.initials: MN
authors.lastname: ter Borg
authors.forename: Dicky
authors.initials: D
authors.lastname: Lindenbergh-Kortleve
authors.forename: Lise Torp
authors.initials: LT
authors.lastname: Jensen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kooy-Winkelaar
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Edward E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.forename: Ludvig M
authors.initials: LM
authors.lastname: Sollid
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.forename: Janneke N
authors.initials: JN
authors.lastname: Samsom
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology; D005903:Gliadin / Q000276:immunology* / Q000494:pharmacology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008643:Mesentery; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006683:HLA-DQ Antigens; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin; D005903:Gliadin