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Role of Thrombospondin-1 in T Cell Response to Ocular Pigment Epithelial Cells^1,2

Yuri Futagami^*, Sunao Sugita^3,*, Jose Vega, Kazuhiro Ishida, Hiroshi Takase^*, Kazuichi Maruyama, Hiroyuki Aburatani and Manabu Mochizuki^*

^* Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan, Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, Department of Ophthalmology, Kobe City General Hospital, Kobe, Japan; and Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan

Ocular pigment epithelium (PE) cells promote the generation of T regulators (PE-induced Treg cells). Moreover, T cells exposed to PE acquire the capacity to suppress the activation of bystander T cells via TGF. Membrane-bound TGF on iris PE cells interacts with TGF receptors on T cells, leading to the conversion of T cells to CD8⁺ Treg cells via a cell contact-dependent mechanism. Conversely, soluble forms of TGF produced by retinal PE cells can convert CD4⁺ T cells into Treg cells in a manner that is independent of cell contact. In this study, we looked at the expression of immunoregulatory factors (TGF, thrombospondins, CD59, IL-1 receptor antagonist, etc.) in PE cells as identified via an oligonucleotide microarray. Several thrombospondin-binding molecules were detected, and thus we focused subsequent analyses on thrombospondins. Via the conversion of latent TGF to an active form that appears to be mediated by thrombospondin 1 (TSP-1), cultured iris PE and retinal PE cells induce a PE-induced Treg cell fate. After conversion, both ocular PE and PE-induced Treg cells express TSP-1. Regulatory T cell generation was amplified when the T cells also expressed TSP-1. In addition, PE-induced Treg cells significantly suppressed activation of bystander T cells via TSP-1. These results strongly suggest that the ability of ocular PE and PE-induced Treg cells to suppress bystander T cells depends on their capacity to produce TSP-1. Thus, intraocular TSP-1 produced by both ocular parenchymal cells and regulatory T cells is essential for immune regulation in 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, and a Grant-in-Aid for Young Scientists (B) 18791263 of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

² The microarray data presented in this article have been submitted to the Gene Expression Omnibus database repository under accession number GSE5134.

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, Japan. E-mail address: sunaoph{at}tmd.ac.jp

⁴ Abbreviations used in this paper: PE, pigment epithelium; ADAMTS, A disintegrin-like and metalloproteinase domain with thrombospondin; CBPE, ciliary body PE; CE, conjunctiva epithelium; EAU, experimental autoimmune uveitis; EIU, endotoxin-induced uveitis; IPE, iris PE; IRBP, interphotoreceptor retinoid-binding protein; MMP, metalloproteinase; RPE, retinal PE; 3TSR, TSP-1 type 1 repeat (3x) recombinant protein; TIMP, tissue inhibitor of metalloproteinase; Treg, T regulator; TSP-1/-2, thrombospondin 1 or 2; DN TGF RII, dominant negative TGF type II receptor.

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