The recognition by the immune system of autoantigen expressed by intestinal epithelial cells (IEC) has yet to be studied. Moreover, how tolerance is maintained to intestine-specific antigens is unknown. A new model system will be utilized to address these issues. IEC-specific transgenic expression of a non-secreted form of ovalbumin as a model antigen has been accomplished. Preliminary results demonstrate that CD8 T cell recognition of this antigen results in immune destruction. The severity of disease is dependent on the amount of antigen expressed. In addition, tolerance induction to IEC autoantigen occurs apparently as a result of absorption of protein derived from IEC turnover. This model will allow us to determine the overall consequence of immune system recognition of intestine-specific antigen.
The aims of this proposal are:
Specific aim 1. To determine the mechanism of enterocyte damage by antigen-specific CD8 T cells. The molecular mechanisms of target organ damage will be defined.
Specific Aim 2. To determine the consequence of CD8 and CD4 T cell reactivity in large intestinal epithelial cell antigen. The transgenic system will be modified to express antigen in large intestine epithelium and to provide inducible antigen expression.
Specific aim 3. To determine the role of TCRgammadelta cells and keratinocyte growth factor in intestinal tissue repair. We will examine whether TCRgammadelta cells, which make up a large proportion of epithelial T cells and produce KGF, are involved in repair of damaged epithelium.
