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Urinary Bladder Epithelium Antigen Induces CD8⁺ T Cell Tolerance, Activation, and Autoimmune Response¹

Department of Urology, University of Iowa Roy J. and Lucille A. Carven College of Medicine, Iowa City, IA 52242

The effort to explore the specific autoimmune mechanisms of urinary bladder has long been hindered due to a lack of proper animal models. To better elucidate this issue, we developed a novel line of transgenic (Tg) mice, designated as URO-OVA mice, that express the model Ag OVA as a "self"-Ag on the bladder epithelium. URO-OVA mice are naturally tolerant to OVA and show no response to OVA stimulation. Adoptive transfer of naive OVA-specific T cells showed cell proliferation, activation, and infiltration but no bladder histopathology. In contrast, adoptive transfer of activated OVA-specific T cells induced OVA-mediated histological bladder inflammation. Increased mast cells and up-regulated mRNA expressions of TNF-, nerve growth factor, and substance P precursor were also observed in the inflamed bladder. To further facilitate bladder autoimmunity study, we crossbred URO-OVA mice with OVA-specific CD8⁺ TCR Tg mice (OT-I mice) to generate a dual Tg line URO-OVA/OT-I mice. The latter mice naturally acquire clonal deletion for autoreactive OT-I CD8⁺ T cells (partial deletion in the thymus and severe deletion in the periphery). Despite this clonal deletion, URO-OVA/OT-I mice spontaneously develop autoimmune cystitis at 10 wk of age. Further studies demonstrated that the inflamed bladder contained infiltrating OT-I CD8⁺ T cells that had escaped clonal deletion and gained effector functions before developing histological bladder inflammation. Taken together, we demonstrate for the first time that the bladder epithelium actively presents self-Ag to the immune system and induces CD8⁺ T cell tolerance, activation, and autoimmune response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant RO1DK066079 and Department of Defense Peer Reviewed Medical Research Program Award W81XWH-04-1-0070 (to Y.L.).

² Address correspondence and reprint requests to Dr. Yi Luo, Department of Urology, University of Iowa, 3202 Medical Education and Research Facility, 375 Newton Road, Iowa City, IA 52242-1087. E-mail address: yi-luo{at}uiowa.edu

³ Abbreviations used in this paper: Tg, transgenic; Ad-OVA, OVA-delivering recombinant adenovirus; B6, C57BL/6 mice; BLN, bladder-draining lymph node; hTrfR, human transferrin receptor; NGF, nerve growth factor; NLN, nondraining inguinal lymph node; RIP, rat insulin promoter; UPII, uroplakin II; VEGF, vascular endothelia growth factor.