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γδ T cells as a major source of IL-17 production during age-dependent RPE degeneration.

Significance statement:

As early as 1980s, T lymphocyte infiltration has been reported in age-related macular degeneration (AMD) eyes correlating with neovascularization and retinal pigment epithelium atrophy, both of which are hallmarks of AMD.  On this issue of Key Scientific Article, Dr. Zhenyang Zhao and colleagues for the first time reported a special subpopulation of lymphocytes, the γδ -T cells, robustly upregulated in the eyes of high-fat diet Nrf2-/- mice, which presented cardinal features of human AMD. Distinct functional changes are observed in these cells as a major source of ocular interleukin-17 (IL-17), which has been reported in high level in human AMD subjects and other diseases such as rheumatoid arthritis and psoriasis. Considering the other prevailing hypothesis of AMD as a disease with disrupted innate immunity, their novel finding enlightens the possibility of cell-mediated immunity as the key event during the AMD pathogenesis. Furthermore, their discovery inspires the future AMD treatment, which can involve γδ -T cells modulation through cytokines or chemicals or even adoptive transfer of autologous in vitro proliferated γδ -T cells as a target immune suppressor to quench the inflammation in AMD eyes.

Figure legend

Significant increase of IL-17 producing {Gamma}{Delta}-T cells in the eyes of high fat diet treated Nrf2-/- mice comparing to wild type strain.

 

 

γδ T cells as a major source of IL-17 production during age-dependent RPE degeneration.. Global Medical Discovery

 

 

 

 

 

 

 

Zhao Z1, Xu P1, Jie Z2, Zuo Y1, Yu B1, Soong L2, Sun J2, Chen Y1, Cai J3. Invest Ophthalmol Vis Sci. 2014 ;55(10):6580-9.

1Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States.and

2Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States.and

3Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas, United States Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, United States.

 

Abstract

PURPOSE:

Chronic inflammation is a key factor contributing to the progression of age-related macular degeneration (AMD). The goals of the current study were to develop an improved mouse model with retinal pathologic features similar to those of AMD and to characterize the immunoreactive cells in the outer retina and choroid during degeneration of the retinal pigment epithelium (RPE).

METHODS:

Mice deficient in nuclear erythroid 2-related factor 2 (Nrf2) at 12 months of age were fed a high-fat, cholesterol-rich diet for up to 16 weeks. Ocular phenotype was monitored by optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) in live animals, and was further validated by retinal histopathology. Immunofluorescence staining of either cryosections or RPE flat mounts was used to define immunoreactive cells. Flow cytometry analyses were further performed to define the subsets of intraocular T lymphocytes.

RESULTS:

After 16 weeks on a high-fat (HF) diet, 58% of the eyes from Nrf2-/- mice had progression of retinal lesions. Major histocompatibility complex class II (MHC II)-positive microglia, FoxP3+ regulatory T cells (Tregs), and CD3+ IL-17-producing T cells were detected in either the retina or sub-RPE space. Flow cytometry analyses further revealed that most of the IL-17-producing cells were CD3+ CD4- TCRγδ + cells.

CONCLUSIONS:

The results suggest that the T cell-mediated immune responses played important roles in controlling the progression of AMD-like phenotype in Nrf2-deficient mice.

Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

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