Autoimmune-mediated intestinal inflammation-impact and regulation of antigen-specific CD8+ T cells.

Abstract

BACKGROUND & AIMS:

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: Astrid Maria Westendorf, Diana Fleissner, Stefanie Deppenmeier, Achim Dieter Gruber, Dunja Bruder, Wiebke Hansen, Roland Liblau, Jan Buer
• Journal: Gastroenterology (Gastroenterology) Vol. 131 Issue 2 Pg. 510-24 (Aug 2006) ISSN: 0016-5085 [Print] United States
• PMID: 16890605 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Animals
• Autoimmunity
• CD4-Positive T-Lymphocytes (immunology, pathology)
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Cell Movement
• Disease Progression
• Enteritis (immunology, pathology)
• Flow Cytometry
• Intestinal Mucosa (immunology, pathology)
• Lymphocyte Activation (immunology)
• Mice
• Mice, Transgenic
• Phenotype