Abstract
Purpose :
We previously reported that choroidal γδ T cells protected the retinal pigment epithelium (RPE) from oxidative injury. Aryl hydrocarbon receptor (AhR) is a key transcription factor for the differentiation and function of interleukin 17 (IL-17)-producing T cells. The goal of the current project is to examine the roles of AhR and IL-17+γδ T cells in acute and chronic toxicity models of RPE injury.
Methods :
AhR-floxed mice were crossed with transgenic mice with Cre expression driven by the RAR-related orphan receptor gamma (Rorc) promoter, to generate AhR knockout in IL-17-producing T cells (Rorc-Ahr KO). Flow cytometry analysis was conducted to verify the IL-17+γδ T deficiency. Rorc-Ahr KO mice were either treated with sodium iodate or fed on a high-fat, cholesterol-rich diet for 6 weeks to induce acute or chronic RPE injury. Optical coherence tomography (OCT), fundus photography, and electroretinogram (ERG) were used in live animals to determine ocular phenotype. Microglia activation was assessed by immunofluorescence staining of cryosections or RPE flat mounts.
Results :
AhR deficiency led to impaired IL-17 production in γδ T cells. In the chronic RPE toxicity model, the conditional knockout mice had a higher number and more extensive area of subretinal IBA-1+ microglia infiltration as indicated by immunostaining on RPE flat-mounts or retinal cryosections. Rorc-Ahr KO had focal RPE pigment loss and atrophy, especially in the peripheral region. Consistent with the pathology findings, Rorc-Ahr KO had reduced scotopic a- and b-wave responses. In the acute toxicity model, fundus photography, OCT, and quantification of RPE flat mounts showed more severe damage in the conditional knockouts.
Conclusions :
Deficiency in IL-17 production in choroidal γδ T cells increased the sensitivity to RPE injury, suggesting IL-17 plays a protective role by controlling microglial activation.
This is a 2021 ARVO Annual Meeting abstract.