Fachbereich Veterinärmedizin



    Autoimmune-mediated Intestinal Inflammation-impact and Regulation of Antigen-specific CD8+ T Cells (2006)

    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Westendorf, Astrid Maria
    Fleissner, Diana
    Deppenmeier, Stefanie
    Gruber, Achim Dieter
    Bruder, Dunja
    Hansen, Wiebke
    Liblau, Roland
    Buer, Jan
    Gastroenterology; 131(2) — S. 510–524
    ISSN: 0016-5085
    Pubmed: 16890605
    Institut für Tierpathologie

    Robert-von-Ostertag-Str. 15
    Gebäude 12
    14163 Berlin
    Tel.+49 30 838 62450 Fax.+49 30 838 62522

    Abstract / Zusammenfassung

    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.

    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.

    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.

    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.