Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Immunol. Jul 27, 2016; 6(2): 105-118
Published online Jul 27, 2016. doi: 10.5411/wji.v6.i2.105
Regulatory T cells suppress autoreactive CD4+ T cell response to bladder epithelial antigen
Wu-Jiang Liu, Yi Luo
Wu-Jiang Liu, Yi Luo, Department of Urology, University of Iowa Carver College of Medicine, Iowa City, IA 52242-1087, United States
Author contributions: Liu WJ performed the research and analyzed the data; Luo Y designed the research; both authors wrote and revised the paper and approved the final version of the article to be published.
Supported by The National Institutes of Health to Luo Y, No. RO1DK066079.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the University of Iowa Institutional Animal Care and Use Committee (protocol number 0307991).
Conflict-of-interest statement: The authors declare no conflict of interests.
Data sharing statement: Technical information, data analysis and model organisms are available from the corresponding author at yi-luo@uiowa.edu.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yi Luo, MD, PhD, Associate Professor of Urology, Department of Urology, University of Iowa Carver College of Medicine, 3204 MERF, 375 Newton Road, Iowa City, IA 52242-1087, United States. yi-luo@uiowa.edu
Telephone: +1-319-3359835 Fax: +1-319-3534556
Received: March 15, 2016
Peer-review started: March 17, 2016
First decision: April 18, 2016
Revised: April 26, 2016
Accepted: June 27, 2016
Article in press: June 29, 2016
Published online: July 27, 2016
Processing time: 127 Days and 14.3 Hours
Abstract

AIM: To investigate the role of regulatory T (Treg) cells in CD4+ T cell-mediated bladder autoimmune inflammation.

METHODS: Urothelium-ovalbumin (URO-OVA)/OT-II mice, a double transgenic line that expresses the membrane form of the model antigen (Ag) OVA as a self-Ag on the urothelium and the OVA-specific CD4+ T cell receptor specific for the I-Ab/OVA323-339 epitope in the periphery, were developed to provide an autoimmune environment for investigation of the role of Treg cells in bladder autoimmune inflammation. To facilitate Treg cell analysis, we further developed URO-OVAGFP-Foxp3/OT-II mice, a derived line of URO-OVA/OT-II mice that express the green fluorescent protein (GFP)-forkhead box protein P3 (Foxp3) fusion protein.

RESULTS: URO-OVA/OT-II mice failed to develop bladder inflammation despite the presence of autoreactive CD4+ T cells. By monitoring GFP-positive cells, bladder infiltration of CD4+ Treg cells was observed in URO-OVAGFP-Foxp3/OT-II mice. The infiltrating Treg cells were functionally active and expressed Treg cell effector molecule as well as marker mRNAs including transforming growth factor-β, interleukin (IL)-10, fibrinogen-like protein 2, and glucocorticoid-induced tumor necrosis factor receptor (GITR). Studies further revealed that Treg cells from URO-OVAGFP-Foxp3/OT-II mice were suppressive and inhibited autoreactive CD4+ T cell proliferation and interferon (IFN)-γ production in response to OVA Ag stimulation. Depletion of GITR-positive cells led to spontaneous development of bladder inflammation and expression of inflammatory factor mRNAs for IFN-γ, IL-6, tumor necrosis factor-α and nerve growth factor in URO-OVAGFP-Foxp3/OT-II mice.

CONCLUSION: Treg cells specific for bladder epithelial Ag play an important role in immunological homeostasis and the control of CD4+ T cell-mediated bladder autoimmune inflammation.

Keywords: Bladder; Autoimmunity; Regulatory T cell; CD4+ T cells; Antigen

Core tip: Evidence suggests that autoimmune inflammation may cause interstitial cystitis/bladder pain syndrome (IC/BPS) in subgroups of patients. However, the role of regulatory T (Treg) cells in the control of bladder autoimmunity has not yet been identified. In this study we developed novel transgenic autoimmune cystitis models and demonstrated that Treg cells specific for bladder epithelial Ag play an important role in immunological homeostasis and the control of CD4+ T cell-mediated bladder autoimmune inflammation. Our results suggest that loss of functional Treg cells may contribute to IC/BPS pathology in subgroups of patients.