title: CD4+ T cell mediated intestinal immunity: chronic inflammation versus immune regulation.
abstract: BACKGROUND
  Several studies have suggested that chronic inflammatory bowel disease may be a consequence of antigen specific recognition by appropriate T cells which expand and induce immunopathology.
  
  
  OBJECTIVE
  We wished to investigate whether autoreactive CD4+ T cells can initiate the disease on recognition of enterocyte specific antigens directly and if induction of mucosal tolerance occurs.
  
  
  METHODS
  Transgenic mice (VILLIN-HA) were generated that showed specific expression of haemagglutinin from influenza virus A exclusively in enterocytes of the intestinal epithelium. To investigate the impact of enterocyte specific haemagglutinin expression in an autoimmune environment, we mated VILLIN-HA mice with T cell receptor (TCR)-HA mice expressing an alpha/beta-TCR, which recognises an MHC class II restricted epitope of haemagglutinin, and analysed the HA specific T cells for induction of autoimmunity or tolerance.
  
  
  RESULTS
  In VILLIN-HAxTCR-HA mice, incomplete central deletion of HA specific lymphocytes occurred. Peripheral HA specific lymphocytes showed an activated phenotype and increased infiltration into the intestinal mucosa, but not into other organs of double transgenic mice. Enterocyte specific lamina propria lymphocytes showed a dose dependent proliferative response on antigen stimulation whereas the proliferative capacity of intraepithelial lymphocytes was reduced. Mucosal lymphocytes from VILLIN-HAxTCR-HA mice secreted lower amounts of interferon gamma and interleukin (IL)-2 but higher levels of tumour necrosis factor alpha, monocyte chemoattractant protein 1, and IL-6. Mucosal immune reactions were accompanied by broad changes in the gene expression profile with expression of proinflammatory genes, but strikingly also a remarkable set of genes discussed in the context of peripheral induction of regulatory T cells, including IL-10, Nrp-1, and Foxp3.
  
  
  CONCLUSIONS
  Enterocyte specific antigen expression is sufficient to trigger a specific CD4+ T cell response leading to mucosal infiltration. In our model, progression to overt clinical disease was counteracted most likely by induction of regulatory T cells.
authors.affiliation: Department of Cell Biology and Immunology, German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Westendorf
authors.forename: M
authors.initials: M
authors.lastname: Templin
authors.forename: R
authors.initials: R
authors.lastname: Geffers
authors.forename: S
authors.initials: S
authors.lastname: Deppenmeier
authors.forename: A D
authors.initials: AD
authors.lastname: Gruber
authors.forename: M
authors.initials: M
authors.lastname: Probst-Kepper
authors.forename: W
authors.initials: W
authors.lastname: Hansen
authors.forename: R S
authors.initials: RS
authors.lastname: Liblau
authors.forename: F
authors.initials: F
authors.lastname: Gunzer
authors.forename: D
authors.initials: D
authors.lastname: Bruder
authors.forename: J
authors.initials: J
authors.lastname: Buer
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D020895:Enterocytes / Q000276:immunology; D020869:Gene Expression Profiling / Q000379:methods; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D018928:Immunity, Mucosal; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic
chemical_list: D001324:Autoantigens; D016207:Cytokines; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C483468:hemagglutinin, human influenza A virus