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.
Similar content being viewed by others
References
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.
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.
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.
Moreland LW, Curtis JR. Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms. Semin Arthritis Rheum. 2009;39:132–43.
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.
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.
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.
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.
Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004;21:467–76.
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.
De Vos AF, Hoekzema R, Kijlstra A. Cytokines and uveitis, a review. Curr Eye Res. 1992;11:581–97.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Sugita S. Role of ocular pigment epithelial cells in immune privilege. Arch Immunol Ther Exp (Warsz). 2009;57:263–8.
Caspi RR, Roberge FG, Nussenblatt RB. Organ-resident, nonlymphoid cells suppress proliferation of autoimmune T-helper lymphocytes. Science. 1987;237:1029–32.
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.
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.
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.
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.
Wenkel H, Streilein JW. Evidence that retinal pigment epithelium functions as an immune-privileged tissue. Invest Ophthalmol Vis Sci. 2000;41:3467–73.
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.
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.
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.
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.
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.
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.
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.
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.
Acknowledgments
We would like to thank Mrs. Ikuyo Yamamoto for her expert technical assistance. This work was supported by Scientific Research (C) 20592073 and Grants-in-Aid for Young Scientists (B) 21791671 and 21791672 of the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Sugita, S., Horie, S., Yamada, Y. et al. Suppression of interleukin-17-producing T-helper 17 cells by retinal pigment epithelial cells. Jpn J Ophthalmol 55, 565–575 (2011). https://doi.org/10.1007/s10384-011-0064-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10384-011-0064-9