Urinary bladder epithelium antigen induces CD8+ T cell tolerance, activation, and autoimmune response.
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-alpha, 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.
Liu
Wujiang
W
Department of Urology, University of Iowa Roy J. and Lucille A. Carven College of Medicine, Iowa City, IA 52242, USA.
Evanoff
David P
DP
Chen
Xiaohong
X
Luo
Yi
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003556:Cystitis / Q000235:genetics / Q000276:immunology*; D004848:Epithelium / Q000737:chemistry / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D014162:Transfection; D001743:Urinary Bladder / Q000737:chemistry / Q000276:immunology* / Q000473:pathology
D001324:Autoantigens; D010047:Ovalbumin