Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury

Abstract

γδ T cells located near the epithelial barrier are integral components of local inflammatory and innate immune responses. We have previously reported the presence of choroidal γδ T cells in a model of chronic degeneration of the retinal pigment epithelium (RPE). The goals of the current study were to further define the functions of choroidal γδ T cells and to explore the underlying mechanisms of their action. Our data demonstrate that choroidal γδ T cells are activated by RPE injury in response to NaIO treatment, and that they express genes that encode immunosuppressive cytokines, such as IL-4 and IL-10. γδ-T-cell-deficient mice developed profound RPE and retinal damage at doses that caused minimal effects in wild-type mice, and adoptive transfer of γδ T cells prevented sensitization. Intravitreal injection of IL-4 and IL-10 ameliorated RPE toxicity that was induced by NaIO coculture of γδ T cells with RPE explants activated the production of anti-inflammatory cytokines an aryl hydrocarbon receptor (AhR)-dependent mechanism. AhR deficiency abolished the protective effects of γδ T cells after adoptive transfer. Collectively, these findings define important roles for choroid γδ T cells in maintaining tissue homeostasis in the outer retina.-Zhao, Z., Liang, Y., Liu, Y., Xu, P., Flamme-Wiese, M. J., Sun, D., Sun, J., Mullins, R. F., Chen, Y., Cai, J. Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury.

A Perspective of AMD Through the Eyes of Immunology

“…Understanding whether adaptive pathways elicit proinflammatory or regulatory functions or represent bystander effects remains limited, in part due to the lack of functional intraocular lymphatics and tangible evidence of direct B-or T-cell involvement at sites of neovascular or geographic lesions. Notwithstanding, reports confirm the presence of T-cell subsets in human choroid, 135,136 as well as the potential for interplay between innate and adaptive immunity, including increased levels of C5a 137 and elevated levels of IL-22 and IL-17. 138 Furthermore, autoantibodies (AAbs) targeting proteins involved in autophagy, immunomodulation, and protection from oxidative stress and apoptosis are detected in AMD patient sera, including during early stage disease.…”

MTOR‐initiated metabolic switch and degeneration in the retinal pigment epithelium

“…Fundus photographs were taken with a Micron-IV camera (Phoenix Research Laboratories, Pleasanton, CA) with cornea-contacting lens. 29 Spectral-domain optical coherence tomography (OCT) scan was performed on a Bioptigen Envisu Imaging System (Leica Microsystems Inc, Buffalo Grove, IL, USA) with a mouse retina lens.…”

“…Ten sections from the perioptic nerve area that spanned a distance of ∼150 μm were picked for quantification of the number of ONL nuclei. 29 For immunofluorescence staining, sagittal cryosections (8 μm thickness) prepared from the cornea to the optic nerve or whole-mount tissues of RPE/choroid were used. 18 After blocking in phosphate-buffered saline (PBS) with 10% of fetal bovine serum (FBS) (v/v) and 0.5% of Triton X-100 (v/v), the tissues were incubated with primary antibodies followed by Alexa Fluor-conjugated secondary antibodies (Thermo Fisher Scientific).…”

“…Images were acquired with a Carl Zeiss AxioVision microscope equipped with ApoTome (Zeiss, Jena, Germany). 29…”

Potential Role of Myeloid-Derived Suppressor Cells (MDSCs) in Age-Related Macular Degeneration (AMD)

“…Retinal infiltration of IL-17-producing γδ-T cells was also detected in mice deficient in anti-oxidant system-regulating nuclear erythroid 2-related factor 2 (Nrf2) exposed to a high-fat, cholesterol-rich diet (59). The findings of deleterious effects are contradictory to the role of γδ-T cells as intraepithelial lymphocyte (IEL)-like cells with protective functions upon inflammatory environment and RPE degeneration (66). The outcome is probably related to local conditions, since inflammasome-associated cytokine IL-1β and the alarmin protein high-mobility group box 1 (HMGB1) are capable of promoting IL-17 expression by γδ-T cells (67).…”