Dataset Information

PD-1⁺ melanocortin receptor dependent-Treg cells prevent autoimmune disease.

ABSTRACT: Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen. The melanocortin 5 receptor (MC5r) and adenosine 2?A receptor (A2Ar) are required for induction of post-EAU regulatory T cells (Tregs) which provide resistance to EAU. We show that blocking the PD-1/PD-L1 pathway prevented suppression of EAU by post-EAU Tregs. A2Ar induction of PD-1⁺FoxP3⁺ Tregs in uveitis patients was similar compared to healthy controls, but was significantly reduced with melanocortin stimulation. Further, lower body mass index correlated with responsiveness to stimulation of this pathway. These observations indicate an importance of the PD-1/PD-L1 pathway to provide resistance to relapsing uveitis and shows a reduced capacity of uveitis patients to induce Tregs when stimulated through melanocortin receptors, but that it is possible to bypass this part of the pathway through direct stimulation of A2Ar.

SUBMITTER: Muhammad F

PROVIDER: S-EPMC6858311 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PD-1+ melanocortin receptor dependent-Treg cells prevent autoimmune disease.

Muhammad Fauziyya F Wang Dawei D Montieth Alyssa A Lee Stacey S Preble Janine J Foster C Stephen CS Larson Theresa A TA Ding Kai K Dvorak Justin D JD Lee Darren J DJ

Scientific reports 20191115 1

Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis marked by ocular autoantigen-specific regulatory immunity in the spleen. The melanocortin 5 receptor (MC5r) and adenosine 2 A receptor (A2Ar) are required for induction of post-EAU regulatory T cells (Tregs) which provide resistance to EAU. We show that blocking the PD-1/PD-L1 pathway prevented suppression of EAU by post-EAU Tregs. A2Ar induction of PD-1+FoxP3+ Tregs in uveitis patients ...[more]

PMID: 31729418

Similar Datasets

Project description:The melanocortin system plays an essential role in the regulation of immune activity. The anti-inflammatory microenvironment of the eye is dependent on the expression of the melanocortin-neuropeptide alpha-melanocyte stimulating hormone (α-MSH). In addition, the melanocortin system may have a role in retinal development and retinal cell survival under conditions of retinal degeneration. We have found that treating experimental autoimmune uveitis (EAU) with α-MSH suppresses retinal inflammation. Also, this augmentation of the melanocortin system promotes immune tolerance and protection of the retinal structure. The benefit of α-MSH-therapy appears to be dependent on different melanocortin receptors. Therefore, we treated EAU mice with α-MSH-analogs with different melanocortin-receptor targets. This approach demonstrated which melanocortin-receptors suppress inflammation, preserve retinal structure, and induce immune tolerance in uveitis. At the chronic stage of EAU the mice were injected twice 1 day apart with 50 μg of α-MSH or an α-MSH-analog. The α-MSH-analogs were a pan-agonist PL8331, PL8177 (potent MC1r-only agonist), PL5000 (a pan-agonist with no MC5r functional activity), MT-II (same as PL5000) and PG901 (MC5r agonist, but also an antagonist to MC3r, and MC4r). Clinical EAU scores were measured until resolution in the α-MSH-treated mice, when the eyes were collected for histology, and spleen cells collected for retinal-antigen-stimulated cytokine production. Significant suppression of EAU was seen with α-MSH or PL8331 treatment. This was accompanied with significant preservation of retinal structure. A similar effect was seen in EAU-mice that were treated with PL8177, except the suppression of EAU was temporary. In EAU mice treated with PL5000, MTII, or PG901, there was no suppression of EAU with a significant loss in whole retina and outer-nuclear layer thickness. There was significant suppression of IL-17 with induction of IL-10 by retinal-antigen stimulated spleen T cells from EAU mice treated with α-MSH, PL8331, PL8177, or PL5000, but not from EAU mice treated with MT-II, or PG901. Our previous studies show the melanocortin system's importance in maintaining ocular immune privilege and that α-MSH-treatment accelerates recovery and induces retinal-antigen-specific regulatory immunity in EAU. Our current results show that this activity is centered around MC1r and MC5r. In addition, the results suggest that a therapeutic potential to target MC1r and MC5r together to suppress uveitis induces regulatory immunity with potentially maintaining a normal retinal structure.

Dataset Information

PD-1⁺ melanocortin receptor dependent-Treg cells prevent autoimmune disease.

Publications

PD-1<sup>+</sup> melanocortin receptor dependent-Treg cells prevent autoimmune disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets