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

Muhammad, Fauziyya; Wang, Dawei; Montieth, Alyssa; Lee, Stacey; Preble, Janine M.; Foster, C. Stephen; Larson, Thayne R.; Ding, Kai; Dvorak, Justin; Lee, Darren J.

doi:10.1038/s41598-019-53297-w

Cited by 16 publications

(16 citation statements)

References 44 publications

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“…It is worth mentioning that a spontaneous recovery from EAU was observed in mice 75-90 days post-immunization with no further relapse. The main drivers of recovery are APC expressing high levels of A 2A ARs and the melanocortin 5 receptor, whose activation leads to increased CD73 and CD39 expression, with an increase of extracellular Ado concentrations which in turn promotes T reg activation and resolution of uveitis [82]. Based on these conflicting results, caution should be used when planning an A 2A ARs-based therapy for uveitis since whether an agonist or an antagonist will provide the better outcome might depend upon the stage of the disease.…”

Section: The Immunomodulatory Role Of a 2a Ars: Can Its Derailment Plmentioning

confidence: 99%

Adenosine Signaling in Autoimmune Disorders

Magni

Ceruti

2020

Pharmaceuticals

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The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any “danger” condition, when oxygen and energy availability dramatically drops. Therefore, adenosine acts as a retaliatory metabolite to counteract the nucleotide-mediated boost of the immune reaction. Based on this observation, it can be foreseen that the recruitment with selective agonists of the receptors involved in the immunomodulatory effect of adenosine might represent an innovative anti-inflammatory approach with potential exploitation in autoimmune disorders. Quite surprisingly, pro-inflammatory activity exerted by some adenosine receptors has been also identified, thus paving the way for the hypothesis that at least some autoimmune disorders may be caused by a derailment of adenosine signaling. In this review article, we provide a general overview of the roles played by adenosine on immune cells with a specific focus on the development of adenosine-based therapies for autoimmune disorders, as demonstrated by the exciting data from concluded and ongoing clinical trials.

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Section: The Immunomodulatory Role Of a 2a Ars: Can Its Derailment Plmentioning

confidence: 99%

Adenosine Signaling in Autoimmune Disorders

Magni

Ceruti

2020

Pharmaceuticals

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“…A mechanism of ocular immune privilege is the induction of systemic immunity against ocular antigen. We and others have found this regulatory immunity to emerge at resolution of uveitis (10,26,27,33). However, we have found that resolution of uveitis can occur without induction of post-EAU regulatory immunity (12,14).…”

Section: Discussionmentioning

confidence: 80%

“…The aim of this study is to further understand the role of the melanocortin-adenosinergic pathway in the induction of autoimmune uveitis. We have previously reported that the melanocortin-adenosinergic pathway is necessary for the induction of post-EAU regulatory immunity that provides resistance to relapse ( 11 , 14 , 26 , 27 ). Our previous work specifically showed that expression of the melanocortin 5 receptor (MC5r) on the post-EAU antigen presenting cell (APC) is required for activation of post-EAU regulatory T cells that express the adenosine 2A receptor (A2Ar).…”

Section: Resultsmentioning

confidence: 99%

Combined Deficiency of the Melanocortin 5 Receptor and Adenosine 2A Receptor Unexpectedly Provides Resistance to Autoimmune Disease in a CD8+ T Cell-Dependent Manner

et al. 2021

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Regulatory immunity that provides resistance to relapse emerges during resolution of experimental autoimmune uveitis (EAU). This post-EAU regulatory immunity requires a melanocortin 5 receptor (MC5r)-dependent suppressor antigen presenting cell (APC), as shown using a MC5r single knock-out mouse. The MC5r-dependent APC activates an adenosine 2A receptor (A2Ar)-dependent regulatory Treg cell, as shown using an A2Ar single knock-out mouse. Unexpectedly, when MC5r-/- post-EAU APC were used to activate A2Ar-/- post-EAU T cells the combination of cells significantly suppressed EAU, when transferred to EAU mice. In contrast, transfer of the reciprocal activation scheme did not suppress EAU. In order to explain this finding, MC5r-/-A2Ar-/- double knock-out (DKO) mice were bred. Naïve DKO mice had no differences in the APC populations, or inflammatory T cell subsets, but did have significantly more Treg cells. When we examined the number of CD4 and CD8 T cell subsets, we found significantly fewer CD8 T cells in the DKO mice compared to WT and both single knock-out mice. DKO mice also had significantly reduced EAU severity and accelerated resolution. In order to determine if the CD8 T cell deficiency contributed to the resistance to EAU in the DKO mice, we transferred naïve CD8 T cells from WT mice, that were immunized for EAU. Susceptibility to EAU was restored in DKO mice that received a CD8 T cell transfer. While the mechanism that contributed to the CD8 T cell deficiency in the DKO mice remains to be determined, these observations indicate an importance of CD8 T cells in the initiation of EAU. The involvement of CD4 and CD8 T cells suggests that both class I and class II antigen presentation can trigger an autoimmune response, suggesting a much wider range of antigens may trigger autoimmune disease.

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“…A recent study demonstrated that PD-1 + CD25 + CD4 + Treg cells require programmed cell death 1 (PD-1) stimulation through a melanocortin-adenosine pathway to suppress EAU. These Treg cells did not induce suppressor activity in APCs through the PD-1 pathway (57).…”

Section: Advances In the Treatment Of Eaumentioning

confidence: 80%

New Insights Into Immunological Therapy for Retinal Disorders

et al. 2020

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In the twentieth century, a conspicuous lack of effective treatment strategies existed for managing several retinal disorders, including age-related macular degeneration; diabetic retinopathy (DR); retinopathy of prematurity (ROP); retinitis pigmentosa (RP); uveitis, including Behçet's disease; and vitreoretinal lymphoma (VRL). However, in the first decade of this century, advances in biomedicine have provided new treatment strategies in the field of ophthalmology, particularly biologics that target vascular endothelial growth factor or tumor necrosis factor (TNF)-α. Furthermore, clinical trials on gene therapy specifically for patients with autosomal recessive or X-linked RP have commenced. The overall survival rates of patients with VRL have improved, owing to earlier diagnoses and better treatment strategies. However, some unresolved problems remain such as primary or secondary non-response to biologics or chemotherapy, and the lack of adequate strategies for treating most RP patients. In this review, we provide an overview of the immunological mechanisms of the eye under normal conditions and in several retinal disorders, including uveitis, DR, ROP, RP, and VRL. In addition, we discuss recent studies that describe the inflammatory responses that occur during the course of these retinal disorders to provide new insights into their diagnosis and treatment.

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

Cited by 16 publications

References 44 publications

Adenosine Signaling in Autoimmune Disorders

Adenosine Signaling in Autoimmune Disorders

Combined Deficiency of the Melanocortin 5 Receptor and Adenosine 2A Receptor Unexpectedly Provides Resistance to Autoimmune Disease in a CD8+ T Cell-Dependent Manner

New Insights Into Immunological Therapy for Retinal Disorders

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