title: Autoimmune-mediated intestinal inflammation-impact and regulation of antigen-specific CD8+ T cells.
abstract: OBJECTIVE
  Few data exist regarding mechanisms of mucosal CD8+ T-cell reactivity to epithelial-specific antigen. To dissect the immunologic mechanisms underlying CD8+ T-cell dysregulation, reactivity to a self-antigen expressed in intestinal epithelium of mice bearing a major histocompatibility complex class I-restricted T-cell receptor specific for this antigen was studied. In addition, antigen-specific regulatory CD4+ T cells induced in vivo were tested to control these autoreactive CD8+ T cells.
  
  
  METHODS
  Transgenic VILLIN-HA mice were mated with CL4-TCR transgenic mice. Alternatively, adoptive transfer of CL4-TCR transgenic CD8+ T cells into VILLIN-HA transgenic mice was performed to mimic spontaneous encounter of neoantigen. Mucosal CD8+ T cells were characterized under different conditions of tolerance, immunopathology, and active immunosuppression.
  
  
  RESULTS
  Transgenic CD8+ T cells from VILLIN-HA x CL4-TCR transgenic mice preferentially migrated and expanded in mucosal lymphoid tissues. Although transgenic CD8+ T cells showed signs of T-cell activation, they failed to cause tissue damage. This was accompanied by the induction/expansion of CD4+ and CD8+, Foxp3-expressing T cells. In contrast, adoptive transfer of naive transgenic CD8+ T cells from CL4-TCR transgenic mice into VILLIN-HA transgenic mice induced severe intestinal inflammation with poor clinical course of disease. Transgenic CD8+ T cells secreted vigorous amounts of proinflammatory cytokines like interferon gamma/tumor necrosis factor alpha. Strikingly, this acute wasting disease was significantly ameliorated by cotransfer of antigen-specific regulatory CD4+ T cells.
  
  
  CONCLUSIONS
  Epithelial-specific antigen expression is sufficient to trigger severe antigen-specific CD8+ T-cell-mediated intestinal inflammation; this might be controlled by antigen-specific regulatory T cells under physiological conditions.
authors.affiliation: Department of Mucosal Immunity, German Research Centre for Biotechnology, Braunschweig, Germany. awe@gbf.de
authors.forename: Astrid Maria
authors.initials: AM
authors.lastname: Westendorf
authors.forename: Diana
authors.initials: D
authors.lastname: Fleissner
authors.forename: Stefanie
authors.initials: S
authors.lastname: Deppenmeier
authors.forename: Achim Dieter
authors.initials: AD
authors.lastname: Gruber
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hansen
authors.forename: Roland
authors.initials: R
authors.lastname: Liblau
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D018450:Disease Progression; D004751:Enteritis / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype