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Japanese Journal of Ophthalmology
Published in: Japanese Journal of Ophthalmology 5/2011

01-09-2011 | Laboratory Investigation

Suppression of interleukin-17-producing T-helper 17 cells by retinal pigment epithelial cells

Authors: Sunao Sugita, Shintaro Horie, Yukiko Yamada, Yuko Kawazoe, Hiroshi Takase, Manabu Mochizuki

Published in: Japanese Journal of Ophthalmology | Issue 5/2011

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Abstract

Purpose

To determine whether retinal pigment epithelial (RPE) cells can inhibit cytokine production by activated T helper (Th) cells.

Methods

Primary RPE cells were cultured from normal C57BL/6 mice. Target bystander T cells were established from normal splenic T cells with anti-CD3 antibodies. T-cell activation was assessed for production of cytokines, determined by ELISA. Production of IL-17 on target T cells was evaluated using oligonucleotide microarray, RT-PCR and flow cytometry. TGFβ small interfering RNA was used to inhibit the RPE cells' inhibitory function.

Results

The cultured RPE cells greatly suppressed the activation of bystander CD4+ T cells in vitro, especially cytokine production by target T helper cells (Th1 cells, Th2 cells and Th17 cells, but not Th3 cells). The cultured RPE cells and RPE supernatants significantly suppressed the IL-17-producing CD4+ T cells and fully suppressed the polarized Th17 cell lines that were induced by recombinant proteins IL-6 and TGFβ2. However, the RPE cells failed to suppress the IL-17-producing T cells in the presence of rIL-6. In addition, the TGFβ produced by the RPE cells suppressed the Th17 cells.

Conclusions

These results indicate that RPE cells have an immunosuppressive effect on Th17-type effector T cells, which highlights a role for ocular resident cells in establishing immune regulation in the eye.
Literature
1.
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.CrossRefPubMed
2.
Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–89.CrossRefPubMed
3.
Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–32.CrossRefPubMed
4.
Moreland LW, Curtis JR. Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms. Semin Arthritis Rheum. 2009;39:132–43.CrossRefPubMed
5.
Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70.CrossRefPubMedPubMedCentral
6.
Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza M, Ayed K. Cytokine profile in Behcet’s disease patients. Relationship with disease activity. Scand J Rheumatol. 2002;31:205–10.CrossRefPubMed
7.
Chi W, Yang P, Li B, Wu C, Jin H, Zhu X, et al. IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease. J Allergy Clin Immunol. 2007;119:1218–24.CrossRefPubMed
8.
Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003;278:1910–4.CrossRefPubMed
9.
10.
Lahmar I, Abou-Bacar A, Abdelrahman T, Guinard M, Babba H, Ben Yahia S, et al. Cytokine profiles in toxoplasmic and viral uveitis. J Infect Dis. 2009;199:1239–49.CrossRefPubMed
11.
De Vos AF, Hoekzema R, Kijlstra A. Cytokines and uveitis, a review. Curr Eye Res. 1992;11:581–97.CrossRefPubMed
12.
Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med. 2007;13:711–8.CrossRefPubMed
13.
Yoshimura T, Sonoda KH, Miyazaki Y, Iwakura Y, Ishibashi T, Yoshimura A, et al. Differential roles for IFN-gamma and IL-17 in experimental autoimmune uveoretinitis. Int Immunol. 2008;20:209–14.CrossRefPubMed
14.
Yoshimura T, Sonoda KH, Ohguro N, Ohsugi Y, Ishibashi T, Cua DJ, et al. Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. Rheumatology (Oxford). 2009;48:347–54.CrossRef
15.
Cui Y, Shao H, Lan C, Nian H, O’Brien RL, Born WK, et al. Major role of gamma delta T cells in the generation of IL-17+ uveitogenic T cells. J Immunol. 2009;183:560–7.CrossRefPubMedPubMedCentral
16.
Tang J, Zhu W, Silver PB, Su SB, Chan CC, Caspi RR. Autoimmune uveitis elicited with antigen-pulsed dendritic cells has a distinct clinical signature and is driven by unique effector mechanisms: initial encounter with autoantigen defines disease phenotype. J Immunol. 2007;178:5578–87.CrossRefPubMed
17.
Sugita S, Streilein JW. Iris pigment epithelium expressing CD86 (B7-2) directly suppresses T cell activation in vitro via binding to cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2003;198:161–71.CrossRefPubMedPubMedCentral
18.
Sugita S, Ng TF, Schwartzkopff J, Streilein JW. CTLA-4+CD8+ T cells that encounter B7-2+ iris pigment epithelial cells express their own B7-2 to achieve global suppression of T cell activation. J Immunol. 2004;172:4184–94.CrossRefPubMed
19.
Sugita S, Futagami Y, Smith SB, Naggar H, Mochizuki M. Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor beta. Exp Eye Res. 2006;83:1459–71.CrossRefPubMed
20.
Sugita S, Usui Y, Horie S, Futagami Y, Aburatani H, et al. T-cell suppression by programmed cell death 1 ligand 1 on retinal pigment epithelium during inflammatory conditions. Invest Ophthalmol Vis Sci. 2009;50:2862–70.CrossRefPubMed
21.
Usui Y, Okunuki Y, Hattori T, Kezuka T, Keino H, Ebihara N, et al. Functional expression of B7H1 on retinal pigment epithelial cells. Exp Eye Res. 2008;86:52–9.CrossRefPubMed
22.
Futagami Y, Sugita S, Vega J, Ishida K, Takase H, Maruyama K, et al. Role of thrombospondin-1 in T cell response to ocular pigment epithelial cells. J Immunol. 2007;178:6994–7005.CrossRefPubMed
23.
Sugita S, Horie S, Nakamura O, Futagami Y, Takase H, Keino H, et al. Retinal pigment epithelium-derived CTLA-2alpha induces TGFbeta-producing T regulatory cells. J Immunol. 2008;181:7525–36.CrossRefPubMed
24.
Sugita S, Horie S, Nakamura O, Maruyama K, Takase H, Usui Y, et al. Acquisition of T regulatory function in cathepsin L-inhibited T cells by eye-derived CTLA-2alpha during inflammatory conditions. J Immunol. 2009;183:5013–22.CrossRefPubMed
25.
Sugita S, Ng TF, Lucas PJ, Gress RE, Streilein JW. B7+ iris pigment epithelium induce CD8+ T regulatory cells; both suppress CTLA-4+ T cells. J Immunol. 2006;176:118–27.CrossRefPubMed
26.
Sugita S. Role of ocular pigment epithelial cells in immune privilege. Arch Immunol Ther Exp (Warsz). 2009;57:263–8.CrossRef
27.
Caspi RR, Roberge FG, Nussenblatt RB. Organ-resident, nonlymphoid cells suppress proliferation of autoimmune T-helper lymphocytes. Science. 1987;237:1029–32.CrossRefPubMed
28.
Thurau SR, Chan CC, Nussenblatt RB, Caspi RR. Oral tolerance in a murine model of relapsing experimental autoimmune uveoretinitis (EAU): induction of protective tolerance in primed animals. Clin Exp Immunol. 1997;109:370–6.CrossRefPubMedPubMedCentral
29.
Avichezer D, Silver PB, Chan CC, Wiggert B, Caspi RR. Identification of a new epitope of human IRBP that induces autoimmune uveoretinitis in mice of the H-2b haplotype. Invest Ophthalmol Vis Sci. 2000;41:127–31.PubMed
30.
Ishida K, Panjwani N, Cao Z, Streilein JW. Participation of pigment epithelium in ocular immune privilege. 3. Epithelia cultured from iris, ciliary body, and retina suppress T-cell activation by partially non-overlapping mechanisms. Ocul Immunol Inflamm. 2003;11:91–105.CrossRefPubMed
31.
Zamiri P, Masli S, Kitaichi N, Taylor AW, Streilein JW. Thrombospondin plays a vital role in the immune privilege of the eye. Invest Ophthalmol Vis Sci. 2005;46:908–19.CrossRefPubMed
32.
Wenkel H, Streilein JW. Evidence that retinal pigment epithelium functions as an immune-privileged tissue. Invest Ophthalmol Vis Sci. 2000;41:3467–73.PubMed
33.
Takase H, Futagami Y, Yoshida T, Kamoi K, Sugita S, Imai Y, et al. Cytokine profile in aqueous humor and sera of patients with infectious or noninfectious uveitis. Invest Ophthalmol Vis Sci. 2006;47:1557–61.CrossRefPubMed
34.
Ohta K, Yamagami S, Taylor AW, Streilein JW. IL-6 antagonizes TGF-beta and abolishes immune privilege in eyes with endotoxin-induced uveitis. Invest Ophthalmol Vis Sci. 2000;41:2591–9.PubMed
35.
Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–86.CrossRefPubMedPubMedCentral
36.
Granstein RD, Staszewski R, Knisely TL, Zeira E, Nazareno R, Latina M, Albert DM. Aqueous humor contains transforming growth factor-beta and a small (less than 3500 daltons) inhibitor of thymocyte proliferation. J Immunol. 1990;144:3021–7.PubMed
37.
Nardelli DT, Burchill MA, England DM, Torrealba J, Callister SM, Schell RF. Association of CD4+CD25+ T cells with prevention of severe destructive arthritis in Borrelia burgdorferi-vaccinated and challenged gamma interferon-deficient mice treated with anti-interleukin-17 antibody. Clin Diagn Lab Immunol. 2004;11:1075–84.PubMedPubMedCentral
38.
Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol. 1998;161:6480–6.PubMed
39.
Peng Y, Han G, Shao H, Wang Y, Kaplan HJ, Sun D. Characterization of IL-17+ interphotoreceptor retinoid-binding protein-specific T cells in experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 2007;48:4153–61.CrossRefPubMedPubMedCentral
40.
Zhang R, Qian J, Guo J, Yuan YF, Xue K. Suppression of experimental autoimmune uveoretinitis by Anti-IL-17 antibody. Curr Eye Res. 2009;34:297–303.CrossRefPubMed
Metadata
Title
Suppression of interleukin-17-producing T-helper 17 cells by retinal pigment epithelial cells
Authors
Sunao Sugita
Shintaro Horie
Yukiko Yamada
Yuko Kawazoe
Hiroshi Takase
Manabu Mochizuki
Publication date
01-09-2011
Publisher
Springer Japan
Published in
Japanese Journal of Ophthalmology / Issue 5/2011
Print ISSN: 0021-5155
Electronic ISSN: 1613-2246
DOI
https://doi.org/10.1007/s10384-011-0064-9

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