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 × 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 γ/tumor necrosis factor α. 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.