Human iris pigment epithelial cells suppress T-cell activation via direct cell contact

Hattori, Takaaki; Kezuka, Takeshi; Usui, Yoshihiko; Okunuki, Yoko; Takeuchi, Masaru; Maruyama, Katsuhiko; Haneda, Mai; Shirato, Shiroaki; Gotô, Hiroshi

doi:10.1016/j.exer.2009.04.004

Cited by 9 publications

(7 citation statements)

References 40 publications

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“…Immune responses to EBOV involve innate and adaptive effector leukocytes 52–55 ; restriction of macrophage, natural killer cell, T and B cell activities by ocular pigment epithelial cells have been described. 56–59 Our data suggest that the immunomodulatory function of the retinal pigment epithelium is maintained during infection with EBOV, which would limit immune responses against the virus. We did not observe sustained changes in expression of TGF-β2, IL-1RN, IL-10, MIF, PTGES3, and FASLG transcript in EBOV-infected ARPE-19 cells, in comparison with mock-infected control cells.…”

Section: Discussionmentioning

confidence: 93%

Retinal Pigment Epithelial Cells are a Potential Reservoir for Ebola Virus in the Human Eye

Smith

Todd

Ashander

et al. 2017

Trans. Vis. Sci. Tech.

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PurposeSuccess of Ebola virus (EBOV) as a human pathogen relates at the molecular level primarily to blockade the host cell type I interferon (IFN) antiviral response. Most individuals who survive Ebola virus disease (EVD) develop a chronic disease syndrome: approximately one-quarter of survivors suffer from uveitis, which has been associated with presence of EBOV within the eye. Clinical observations of post-Ebola uveitis indicate involvement of retinal pigment epithelial cells.MethodsWe inoculated ARPE-19 human retinal pigment epithelial cells with EBOV, and followed course of infection by immunocytochemistry and measurement of titer in culture supernatant. To interrogate transcriptional responses of infected cells, we combined RNA sequencing with in silico pathway, gene ontology, transcription factor binding site, and network analyses. We measured infection-induced changes of selected transcripts by reverse transcription-quantitative polymerase chain reaction.ResultsHuman retinal pigment epithelial cells were permissive to infection with EBOV, and supported viral replication and release of virus in high titer. Unexpectedly, 28% of 560 upregulated transcripts in EBOV-infected cells were type I IFN responsive, indicating a robust type I IFN response. Following EBOV infection, cells continued to express multiple immunomodulatory molecules linked to ocular immune privilege.ConclusionsHuman retinal pigment epithelial cells may serve as an intraocular reservoir for EBOV, and the molecular response of infected cells may contribute to the persistence of live EBOV within the human eye.Translational RelevanceThis bedside-to-bench research links ophthalmic findings in survivors of EVD who suffer from uveitis with interactions between retinal pigment epithelial cells and EBOV.

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Section: Discussionmentioning

confidence: 93%

Retinal Pigment Epithelial Cells are a Potential Reservoir for Ebola Virus in the Human Eye

Smith

Todd

Ashander

et al. 2017

Trans. Vis. Sci. Tech.

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“…Work with human iris pigment epithelial cells in culture has suggested that similar mechanisms are in play, with contact dependant and TGFβ dependant suppression of T-cell proliferation and IFN-γ production (65). Cultured human iris pigment epithelial cells also express PD-L1 and PD-L2, and the PD-1 pathway may be involved in control of immune responses in the human eye, as it is in the mouse (66). Clinical evidence for this comes in the form of drug related uveitis which can be triggered by checkpoint inhibitor therapy used in the treatment of a range of solid and haematological cancers (67,68).…”

Section: Irismentioning

confidence: 99%

The Cellular Composition of the Uveal Immune Environment

et al. 2021

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The uveal tract consists of the iris, the ciliary body and the choroid; these three distinct tissues form a continuous layer within the eye. Uveitis refers to inflammation of any region of the uveal tract. Despite being grouped together anatomically, the iris, ciliary body and choroid are distinct functionally, and inflammatory diseases may affect only one part and not the others. Cellular structure of tissues direct their function, and understanding the cellular basis of the immune environment of a tissue in health, the “steady state” on which the perturbations of disease are superimposed, is vital to understanding the pathogenesis of those diseases. A contemporary understanding of the immune system accepts that haematopoietic and yolk sac derived leukocytes, though vital, are not the only players of importance. An array of stromal cells, connective tissue cells such as fibroblasts and endothelial cells, may also have a role in the inflammatory reaction seen in several immune-mediated diseases. In this review we summarise what is known about the cellular composition of the uveal tract and the roles these disparate cell types have to play in immune homeostasis. We also discuss some unanswered questions surrounding the constituents of the resident leukocyte population of the different uveal tissues, and we look ahead to the new understanding that modern investigative techniques such as single cell transcriptomics, multi-omic data integration and highly-multiplexed imaging techniques may bring to the study of the uvea and uveitis, as they already have to other immune mediated inflammatory diseases.

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“…This is achieved by producing soluble mediators, such as TGF-β [155], α-MSH, and MIF [156], that are also present in the healthy eye. The expression of the membrane-bound PD-L1 was found in the retina, cornea, and iris [157][158][159], but also on UM cells [160]. However, unlike CM, only about 10% of UM primary tumors [99] and 5% of the UM cells in metastatic UM sites express PD-L1, but about 50% of tumor-infiltrating lymphocytes (TILs) express its receptor PD-1 [136].…”

Section: Development Of the Primary Tumor In An Immune-privileged Organmentioning

confidence: 99%

The Role of Immune Checkpoint Blockade in Uveal Melanoma

Wessely

Steeb

Erdmann

et al. 2020

IJMS

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Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.

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Human iris pigment epithelial cells suppress T-cell activation via direct cell contact

Cited by 9 publications

References 40 publications

Retinal Pigment Epithelial Cells are a Potential Reservoir for Ebola Virus in the Human Eye

Retinal Pigment Epithelial Cells are a Potential Reservoir for Ebola Virus in the Human Eye

The Cellular Composition of the Uveal Immune Environment

The Role of Immune Checkpoint Blockade in Uveal Melanoma

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