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Induces TGFβ-Producing T Regulatory Cells1,2
*Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan;
Osaka Prefectural Hospital Organization, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan;
Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan;
Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan;
¶Division of Life Style Diseases and
||Division of Molecular Biology, Institute for Health Sciences, Tokushima Bunri University, Tokushima, Japan; and
#Laboratory of Biochemistry and Radiation Biology, Department of Veterinary Sciences, Faculty of Agriculture, Yamaguchi University, Yamaguchi, Japan
T cells that encounter ocular pigment epithelium in vitro are inhibited from undergoing TCR-triggered activation, and instead acquire the capacity to suppress the activation of bystander T cells. Because retinal pigment epithelial (RPE) cells suppress T cell activation by releasing soluble inhibitory factors, we studied whether soluble factors also promote the generation of T regulatory (Treg) cells. We found that RPE converted CD4+ T cells into Treg cells by producing and secreting CTLA-2
, a cathepsin L (CathL) inhibitor. Mouse rCTLA-2 converted CD4+ T cells into Treg cells in vitro, and CTLA-2 small interfering RNA-transfected RPE cells failed to induce the Treg generation. RPE CTLA-2 induced CD4+CD25+Foxp3+ Treg cells that produced TGFβ in vitro. Moreover, CTLA-2 produced by RPE cells inhibited CathL activity in the T cells, and losing CathL activity led to differentiation to Treg cells in some populations of CD4+ T cells. In addition, T cells in the presence of CathL inhibitor increased the expression of Foxp3. The CTLA-2 effect on Treg cell induction occurred through TGFβ signaling, because CTLA-2 promoted activation of TGFβ in the eye. These results show that immunosuppressive factors derived from RPE cells participate in T cell suppression. The results are compatible with the hypothesis that the eye-derived Treg cells acquire functions that participate in the establishment of immune tolerance in the posterior segment of the eye.
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 U.S. Public Health Service Grant EY 05678 and Scientific Research (B) 1437055, Grant-in-Aid for Young Scientists (B) 18791263 of the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
2 S.S. was the principal investigator, designed and performed experiments, and wrote the manuscript. S.H. established pigment epithelium Treg cells and carried out EAU induction. O.N. performed immunohistochemical, PCR, and in situ hybridization studies. Y.F. performed experiments using the GeneChip microarray. H.T. carried out EAU induction. H.K. performed RT-PCR for Foxp3. H.A. supervised the GeneChip microarray study. N.K. produced CathL inhibitors. Y.Y. produced recombinants and Ab for CTLA-2. M.M. designed and conceptualized the study, and drafted and edited the manuscript.
3 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
4 Abbreviations used in this paper: RPE, retina pigment epithelium; CathB, cathepsin B; CathL, cathepsin L; CBPE, ciliary body pigment epithelium; DN, dominant negative; EAU, experimental autoimmune uveitis; IPE, iris pigment epithelium; qRT-PCR, quantitative RT-PCR; siRNA, small interfering RNA; Treg, T regulatory.
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  S. Sugita, S. Horie, O. Nakamura, K. Maruyama, H. Takase, Y. Usui, M. Takeuchi, K. Ishidoh, M. Koike, Y. Uchiyama, et al. Acquisition of T Regulatory Function in Cathepsin L-Inhibited T Cells by Eye-Derived CTLA-2{alpha} during Inflammatory Conditions J. Immunol., October 15, 2009; 183(8): 5013 - 5022. [Abstract] [Full Text] [PDF]
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