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

Abstract

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-α, 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.

RDP58 inhibits T cell-mediated bladder inflammation in an autoimmune cystitis model

“…Increased mast cells were also observed in the inflamed bladder at later timepoints [31]. In addition to histopathology, the inflamed bladder also showed increased mRNA expression of mast cell inflammatory mediators tumor necrosis factor (TNF)-α and nerve growth factor (NGF) as well as sensory nerve neurotransmitter substance P (SP) precursor [31]. Thus, URO-OVA mice provide an ideal model for the study of bladder-originated autoimmunity and for testing of potential therapeutic agents for autoimmune-associated bladder disorders.…”

“…The inflamed bladder showed clear histopathology including cellular infiltration and epithelial hyperplasia [31]. Increased mast cells were also observed in the inflamed bladder at later timepoints [31]. In addition to histopathology, the inflamed bladder also showed increased mRNA expression of mast cell inflammatory mediators tumor necrosis factor (TNF)-α and nerve growth factor (NGF) as well as sensory nerve neurotransmitter substance P (SP) precursor [31].…”

“…We have demonstrated that URO-OVA mice develop IC-like histological bladder inflammation at day 7 after adoptive transfer of OVA-specific T cells from OT-I mice, a transgenic line expressing the OVA-specific CD8 + T cell receptor (TCR) [31]. The inflamed bladder showed clear histopathology including cellular infiltration and epithelial hyperplasia [31].…”

“…URO-OVA mice (B6 and Thy1.2 background) are a novel urothelial OVA transgenic line developed in our laboratory that provides a unique model for the study of bladder-originated autoimmune inflammation [31]. Female URO-OVA mice (6-8 weeks) were used because of their feasibility for intravesical procedures.…”

“…To facilitate the study of bladder autoimmunity, we recently developed a novel line of transgenic mice, designated as URO-OVA mice, that expresses a membrane form of the model antigen ovalbumin (OVA) as an autoantigen on the bladder epithelium [31]. We have demonstrated that URO-OVA mice develop IC-like histological bladder inflammation at day 7 after adoptive transfer of OVA-specific T cells from OT-I mice, a transgenic line expressing the OVA-specific CD8 + T cell receptor (TCR) [31].…”