CD73 expression in RPE cells is associated with the suppression of conventional CD4 cell proliferation

Song, Chao; Zhou, Shumin; Zang, Kai hong; Kong, Fanting; Liang, Dongchun; Yan, Hua

doi:10.1016/j.exer.2014.05.008

Cited by 7 publications

(6 citation statements)

References 44 publications

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“…This means that the utilization of adenosine by different cell types may produce opposing outcomes in a single disease and that as an autocrine or paracrine stimulus (Blackburn et al, 2009; Zhou et al, 2009), the microenvironment in which adenosine is generated has a critical role in deciding which cell type has priority regarding the use of adenosine. For this reason, cells, including B cells (Kim et al, 2017), retinal pigment epithelium (RPE) (Chen et al, 2014), and breast cancer cells (Jadidi-Niaragh et al, 2016), that control extracellular adenosine generation through membrane-bound CD73 have been widely studied for their immune regulatory effects, especially when they interact with T cells. Here, we wanted to determine if neural cells, particularly neuroglial cells, which are the first to encounter and have intensive interactions with invading T cells, can regulate neuroinflammation through surface-expressed CD73 upon the induction of EAE.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Pro-inflammatory Effect of Downregulated CD73 Expression in EAE Astrocytes

Zhou

Liu

Guo

et al. 2019

Front. Cell. Neurosci.

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CD73, an ectonucleotidase, participates in the regulation of immune responses by controlling the conversion of extracellular AMP to adenosine. In this study, we investigated whether any type of brain cells, especially neuroglia cells, exhibit altered CD73 expression, localization or activity upon experimental autoimmune uveitis (EAU) induction and whether altered CD73 manipulates the activation of effector T cells that interact with such cell types. First, the amount of cell membrane-exposed CD73 was detected by flow cytometry in various types of brain cells collected from either naïve or EAE mice. Compared to that in astrocytes from naïve control mice, the amount of membrane-bound CD73 was significantly decreased in astrocytes from EAE mice, while no significant differences were detected in other cell types. Thereafter, wild-type and CD73 -/- astrocytes were used to study whether CD73 influences the function of inflammatory astrocytes, such as the production of cytokines/chemokines and the activation of effector T cells that interact with astrocytes. The results indicated that the addition of exogenous AMP significantly inhibited cytokine/chemokine production by wild type astrocytes but had no effect on CD73 -/- astrocytes and that the effect of AMP was almost completely blocked by the addition of either a CD73 inhibitor (APCP) or an adenosine receptor A1 subtype (ARA1) antagonist (DPCPX). Although the addition of AMP did not affect CD73 -/- astrocytes, the addition of adenosine successfully inhibited their cytokine/chemokine production. The antigen-specific interaction of astrocytes with invading CD4 cells caused CD73 downregulation in astrocytes from mice that underwent EAE induction. Collectively, our findings support the conclusion that, upon EAE induction, likely due to an interaction with invading CD4 + cells, astrocytes lose most of their membrane-localized CD73; this inhibits the generation of adenosine in the local microenvironment. As adenosine has anti-inflammatory effects on astrocytes and CNS-infiltrating effector T cells in EAE, the downregulation of CD73 in astrocytes may be considered a pro-inflammatory process for facilitating the pathogenesis of EAE.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Pro-inflammatory Effect of Downregulated CD73 Expression in EAE Astrocytes

Zhou

Liu

Guo

et al. 2019

Front. Cell. Neurosci.

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“…In this study, we show that the HSV-1-specific CD73 + CD8 + T cells play crucial role in protection against ocular herpes infection and disease. CD73, an enzyme that convert extracellular AMP into adenosine, is expressed on various types of immune cells, including CD4 + T cells, and binds to the A2A adenosine receptor (A2AR) (76–78). CD73 also plays an important role in regulating T cells migration into infected tissues (76–78, 81).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Functional Signatures of Herpes Simplex Virus–Specific Effector Memory CD73+CD45RAhighCCR7lowCD8+ TEMRA and CD73+CD45RAlowCCR7lowCD8+ TEM Cells Are Associated with Asymptomatic Ocular Herpes

Srivastava

Coulon

Roy

et al. 2018

The Journal of Immunology

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HSV type 1 (HSV-1)-specific CD8 T cells protect from herpes infection and disease. However, the nature of protective CD8 T cells in HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (with no history of clinical herpes disease) remains to be determined. In this study, we compared the phenotype and function of HSV-specific CD8 T cells from HLA-A*02:01-positive ASYMP and symptomatic (SYMP) individuals (with a documented history of numerous episodes of recurrent ocular herpetic disease). We report that although SYMP and ASYMP individuals have similar frequencies of HSV-specific CD8 T cells, the "naturally" protected ASYMP individuals have a significantly higher proportion of multifunctional HSV-specific effector memory CD8 T cells (CD73CD45RACCR7CD8 effector memory RA (T) and CD73CD45RACCR7CD8 effector memory (T) as compared with SYMP individuals. Similar to humans, HSV-1-infected ASYMP B6 mice had frequent multifunctional HSV-specific CD73CD8 T cells in the cornea, as compared with SYMP mice. Moreover, in contrast to wild type B6, CD73 deficient mice infected ocularly with HSV-1 developed more recurrent corneal herpetic infection and disease. This was associated with less functional CD8 T cells in the cornea and trigeminal ganglia, the sites of acute and latent infection. The phenotypic and functional characteristics of HSV-specific circulating and in situ CD73CD8 T cells, demonstrated in both ASYMP humans and mice, suggest a positive role for effector memory CD8 T cells expressing the CD73 costimulatory molecule in the protection against ocular herpes infection and disease. These findings are important for the development of safe and effective T cell-based herpes immunotherapy.

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“…The conversion of AMP to adenosine was measured to assess the enzymatic activity of CD73 in RPE cells and concentrated mediums. Adenosine was detected by a HPLC-based method which was published by us before [8]; and all the detection was performed with EHNA (50 μM), a potent adenosine deaminase (ADA) inhibitor, in the presence to exclude possible adenosine degradation. For cell samples, 5 × 10 4 cells were used to catalyze AMP substrate at the concentration of 1 mM in 100 μl DPBS buffer; after 1 h incubation at 37°C, adenosine in the reaction was detected by HPLC.…”

Section: Cd73 Activity Assaymentioning

confidence: 99%

“…When inflammation happened, RPE cells lost their membrane-localized CD73. This inhibited the conversion of AMP to adenosine, significantly downregulated adenosine's immune suppressive function, and promoted local inflammation [8].…”

Section: Fret Confirmed Cd73-ara1 Interactionmentioning

confidence: 99%

“…treatment of inflammatory factors, RPE cells lost surface CD73, leading to significantly inhibited local adenosine production. Decreased environmental adenosine concentration hindered its immune suppressive effect and promoted experimental autoimmune uveitis (EAU) [8]. Clarifying the mechanism inducing the loss of membrane CD73 in RPE cells could help us understanding local immune disorders as well as finding novel therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

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Multiple steps determine CD73 shedding from RPE: lipid raft localization, ARA1 interaction, and MMP-9 up-regulation

Zhang

Zhou

Liu

et al. 2018

Purinergic Signalling

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Physiologically, retinal pigment epithelium (RPE) expresses high levels of CD73 in their membrane, converting AMP to immune suppressive adenosine, mediates an anti-inflammatory effect. However, after being exposed to inflammatory factors, RPE rapidly becomes CD73-negative cells, which render RPE's immune suppressive function and accelerate local inflammation. Here, we investigated the mechanism leading to the loss of membrane CD73 in RPE. We found the controversy that when membrane CD73 was significantly diminished in inflammatory RPE, Cd73 mRNA levels were not changed at all. It was further verified that, matrix metalloproteinase-9 (MMP-9) mediated the shedding of CD73 from the cell membrane of inflammatory RPE by catalyzing its K547/F548 site. However, MMP-9 could not catalyze uncomplexed CD73, the interaction of CD73 with adenosine receptor A1 subtype (ARA1) is necessary for being catalyzed by MMP-9. After being treated by LPS and TNF-α, the formation of CD73/ARA1 complex in RPE was verified by co-immunoprecipitation and FRET-based assays. It was also revealed that CD73 need to be localized in lipid rafts to be capable of interacting with ARA1, since CD73/ARA1 interaction and CD73 shedding were completely blocked by the addition of lipid raft synthesis inhibitor. As a conclusion, multiple steps are involved in CD73 shedding in RPE, including up-regulation of MMP-9 activity, localization of CD73 in lipid rafts, and the formation of CD73/ARA1 complex. Lipid rafts committed CD73 with high mobility, shuttled CD73 to ARA1 to form a complex, which was capable of being recognized and catalyzed by MMP-9.

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CD73 expression in RPE cells is associated with the suppression of conventional CD4 cell proliferation

Cited by 7 publications

References 44 publications

RETRACTED: Pro-inflammatory Effect of Downregulated CD73 Expression in EAE Astrocytes

RETRACTED: Pro-inflammatory Effect of Downregulated CD73 Expression in EAE Astrocytes

Phenotypic and Functional Signatures of Herpes Simplex Virus–Specific Effector Memory CD73+CD45RAhighCCR7lowCD8+ TEMRA and CD73+CD45RAlowCCR7lowCD8+ TEM Cells Are Associated with Asymptomatic Ocular Herpes

Multiple steps determine CD73 shedding from RPE: lipid raft localization, ARA1 interaction, and MMP-9 up-regulation

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