TIGIT+ A2Ar-Dependent anti-uveitic Treg cells are a novel subset of Tregs associated with resolution of autoimmune uveitis

Muhammad, Fauziyya; Wang, Dawei; McDonald, Trisha; Walsh, Marisa; Drenen, Kayla; Montieth, Alyssa; Foster, C. Stephen; Lee, Darren J.

doi:10.1016/j.jaut.2020.102441

Cited by 16 publications

(27 citation statements)

References 38 publications

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“…It is possible that the 33% of uveitis patients that become chronic (5) do so because of the lack of regulatory immunity that provides resistance to relapse. Our previous observations that stimulation of the melanocortinadenosinergic pathway only induces regulatory T cells in a subset of patients (14,26,34), supports this hypothesis based on our animal model observations. While ocular immune privilege may have evolved to protect the delicate light-gathering tissues of the eye, it is not perfect.…”

Section: Discussionsupporting

confidence: 89%

“…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: 81%

“…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%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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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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“…Adenosine stimulates A2aR on T cells and inhibits expression of NF-κB-regulated cytokines that may impair Treg function or stability, such as IL-2, TNFα, IFNγ, and IL-6 ( Ohta et al, 2012 ; Romio et al, 2011 ; Zarek et al, 2008 ). In experimental autoimmune uveitis, Treg emergence and stability depends on A2aR stimulation ( Muhammad et al, 2020 ). In patients with systemic lupus erythematosus, A2aR activation inhibits classical NF-κB and reduces inflammatory cytokines including IL-6 ( Bortoluzzi et al, 2016 ), and an A2aR agonist reduces IL-6 and increases Tregs ( Zheng and Wang, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses

Saxena

Piao

et al. 2022

Cell Reports

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“…In short, Treg modulate their regulatory function by suppressing cytolysis, modulating dendritic cell (DC) function, and by metabolic competition [74,75]. Recently, it has been reported that a newly discovered Treg subset, TIGIT + Treg, promotes disease remission in autoimmune uveitis and potentially other autoimmune diseases, and this is dependent on the expression of A2Ar [66,76,77]. Treg (CD4 + CD25 hi or CD4 + FoxP3 + ) have been shown to play an important role in protecting against Vogt-Koyanagi-Harada (VKH), ocular BD, JIA-associated uveitis and other NIUs by functionally suppressing Th1 and Th17 cells [66,67,78,79].…”

Section: Importance Of Treg/th17 Cells In Autoimmune Disease and Eaumentioning

confidence: 99%

CD4+ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease

Chen

Lightman

Calder

2021

IJMS

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Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4+ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4+FoxP3+CD25+ regulatory T cells (Tregs) were known to suppress function of effector CD4+ T cells and contribute to resolution of disease. It has been recently reported that some CD4+ T-cell subsets demonstrate shared phenotypes with another CD4+ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these ‘plastic CD4+ T cells’ are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.

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TIGIT+ A2Ar-Dependent anti-uveitic Treg cells are a novel subset of Tregs associated with resolution of autoimmune uveitis

Cited by 16 publications

References 38 publications

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

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

Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses

CD4+ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease

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