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,
Departments of
* Laboratory Medicine and Pathology and
Pediatrics and
Center for Immunology, University of Minnesota, Minneapolis, MN 55455
Using a previously described human keratin 14 (K14) promoter, we
created mice expressing a peptide Ag (OVAp) in epithelial cells of the
skin, tongue, esophagus, and thymus. Double transgenic mice that also
express a TCR specific for this Ag (OT-I) showed evidence for Ag-driven
receptor editing in the thymus. Surprisingly, such mice exhibited a
severe autoimmune disease. In this work we describe the features of
this disease and demonstrate that it is dependent on CD8 T cells.
Consistent with the Ag expression pattern dictated by the human K14
promoter, an inflammatory infiltrate was observed in skin and esophagus
and around bile ducts of the liver. We also observed a high level of
TNF-
in the serum. Given that Ag expression in the thymus induced
development of T cells with dual TCR reactivity, and that dual-reactive
cells have been suggested to have autoimmune potential, we tested
whether they were a causal factor in the disease observed here. We
found that OT-I/K14-OVAp animals on a recombinase-activating
gene-deficient background still suffered from disease. In addition,
OT-I animals expressing OVA broadly in all tissues under a different
promoter did not experience disease, despite having a similar number of
dual-specific T cells. Thus, in this model it would appear that
dual-reactive T cells do not underlie autoimmune pathology. Finally, we
extended these observations to a second transgenic system involving 2C
TCR-transgenic animals expressing the SIY peptide Ag with the hK14
promoter. We discuss the potential relationship between autoimmunity
and self-Ags that are expressed in stratified
epithelium.
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