A spontaneous CD8 T cell-dependent autoimmune disease to an antigen expressed under the human keratin 14 promoter.
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-alpha 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.
McGargill
Maureen A
MA
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Mayerova
Dita
D
Stefanski
Heather E
HE
Koehn
Brent
B
Parke
Evan A
EA
Jameson
Stephen C
SC
Panoskaltsis-Mortari
Angela
A
Hogquist
Kristin A
KA
D000818:Animals; D000941:Antigens / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004527:Egg Proteins / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D015870:Gene Expression; D019672:Genes, T-Cell Receptor; D006801:Humans; D053547:Keratin-14; D007633:Keratins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments; D011401:Promoter Regions, Genetic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism
D000941:Antigens; D004527:Egg Proteins; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; C110366:OVA-8; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007633:Keratins; D010047:Ovalbumin