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during Inflammatory Conditions1
*Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine and Dental Sciences, Tokyo, Japan;
Osaka Prefectural Hospital Organization, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan;
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan;
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan;
¶Division of Molecular Biology, Institute for Health Sciences, Tokushima Bunri University, Tokushima, Japan;
||Department of Cell Biology and Neuroscience, Juntendo University School of Medicine, Tokyo, Japan;
#Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany; and
**Laboratory of Biochemistry and Radiation Biology, Department of Veterinary Sciences, Faculty of Agriculture, Yamaguchi University, Yamaguchi, Japan
Pigment epithelium isolated from the eye possesses immunosuppressive properties such as regulatory T (Treg) cell induction; e.g., cultured retinal pigment epithelium (RPE) converts CD4+ T cells into Treg cells in vitro. RPE constitutively expresses a novel immunosuppressive factor, CTLA-2
, which is a cathepsin L (CathL) inhibitor, and this molecule acts via RPE to induce Treg cells. To clarify CTLA-2’s role in the T cell response to RPE in ocular inflammation, we used the experimental autoimmune uveitis (EAU) animal model to examine this new immunosuppressive property of RPE. In EAU models, TGF-β, but not IFN-
inflammatory cytokines, promotes the up-regulation of the expression of CTLA-2 in RPE. Similarly, CTLA-2 via RPE was able to promote TGF-β production by the CD4+ T cells. The RPE-exposed T cells (RPE-induced Treg cells) greatly produced TGF-β and suppressed bystander effector T cells. There was less expression of CathL by the RPE-exposed T cells, and CathL-inhibited T cells were able to acquire the Treg phenotype. Moreover, CathL-deficient mice spontaneously produced Treg cells, with the increase in T cells potentially providing protection against ocular inflammation. More importantly, CD4+ T cells from EAU in CathL knockout mice or rCTLA-2 from EAU animals were found to contain a high population of forkhead box p3+ T cells. In both EAU models, there was significant suppression of the ocular inflammation. These results indicate that RPE secretes CTLA-2, thereby enabling the bystander T cells to be converted into Treg cells via TGF-β promotion.
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 Grant-in-Aid 18791263 and 20592073 for Scientific Research from the Japan Society for the Promotion of Science.
Author contributions: S.S., who was the principal investigator, designed and performed the experiments, and wrote the manuscript. S.H. and H.T. established the Treg cells and carried out the EAU induction and flow cytometry. O.N. performed the qPCR, Western blotting, and CathL activity analysis. K.M. performed genotyping for KO mice. Y.U. (Dr. Usui) and M.T. carried out the EAU induction in KO mice. K.I. produced anti-CathL Ab. M.K. performed immunohistochemical experiments. Y.U. (Dr. Uchiyama) and C.P. supervised the CathL KO mice. Y.Y. produced recombinants and Ab for CTLA-2. M.M. designed and conceptualized the study, and drafted and edited the manuscript.
2 Address correspondence and reprint requests to Dr. Sunao Sugita, Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail address: sunaoph{at}tmd.ac.jp
3 Abbreviations used in this paper: EAU, experimental autoimmune uveitis; CathL, cathepsin L; EGFP, enhanced GFP; Foxp3, forkhead box p3; IRBP, interphotoreceptor retinoid-binding protein peptide; iTreg, induced T regulatory; KO, knockout; nTreg, naturally occurring T regulatory; PBS-T, PBS that contained 0.01% Tween 20; qRT-PCR, quantitative RT-PCR; RPE, retinal pigment epithelium; Treg, T regulatory; T resp, responder target T cells.
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