High Expression of the Ectonucleotidase CD39 on T Cells from the Inflamed Site Identifies Two Distinct Populations, One Regulatory and One Memory T Cell Population

Moncrieffe, Halima; Nistala, Kiran; Kamhieh, Yasmine; Evans, John M.; Eddaoudi, Ayad; Eaton, Simon; Wedderburn, Lucy R.

doi:10.4049/jimmunol.0803474

Cited by 122 publications

(141 citation statements)

References 49 publications

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“…This supports previous studies where CD39, in combination with other Treg-cell surface markers, identified a population of human FOXP3 + suppressive Treg cells [11,14,43,44].…”

Section: Discussionsupporting

confidence: 79%

Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

et al. 2014

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Human Ag-specific CD4 + T cells can be detected by their dual expression of CD134 (OX40) and CD25 after a 44 hours stimulation with cognate Ag. We show that surface expression of CD39 on Ag-specific cells consistently identifies a substantial population of CD4 + CD25 + CD134 + CD39 + T cells that have a Treg-cell-like phenotype and mostly originate from bulk memory CD4 + CD45RO + CD127 low CD25 high CD39 + Treg cells. Viable, Ag-specific CD25 + CD134 + CD39 + T cells could be expanded in vitro as cell lines and clones, and retained high Forkhead Box Protein 3, CTLA-4 and CD39 expression, suppressive activity and Ag specificity. We also utilised this combination of cell surface markers to measure HIV-Gag responses in HIV + patients before and after anti-retroviral therapy (ART). Interestingly, we found that the percentage of CD39 − cells within baseline CD4 + T-cell responses to HIV-Gag was negatively correlated with HIV viral load pre-ART and positively correlated with CD4 + T-cell recovery over 96 weeks of ART. Collectively, our data show that Ag-specific CD4 + CD25 + CD134 + CD39 + T cells are highly enriched for Treg cells, form a large component of recall responses and maintain a Treg-cell-like phenotype upon in vitro expansion. Identification and isolation of these cells enables the role of Treg cells in memory responses to be further defined and provides a development pathway for novel therapeutics.Keywords: Antigen-specific T cells r CD25 r CD39 r CD134 r FOXP3 r OX40 r Treg cell Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Laura Cook e-mail: lcook@kirby.unsw.edu.au * These authors contributed equally to this work. The current gold standard marker for the study of Treg cells is Forkhead Box Protein 3 (FOXP3), a constitutively expressed nuclear transcription factor, critical for Treg-cell survival and suppressive function [3]. The key limitation of this marker is that viable cells cannot be isolated, as staining for this intracellular protein involves cell permeabilisation. Also, in the context of activation, this marker loses specificity due to transient, activationinduced up-regulation of FOXP3 in human non-Treg cells [4,5]. An alternative, widely used definition of Treg cells is the combined cell surface expression of high levels of CD25 (IL-2Rα) and low levels of CD127 (IL-7Rα) [6]. Whilst >85% of CD127 low CD25 high Treg cells express FOXP3 and are suppressive ex vivo [6], activated Treg cells cannot be isolated with these markers due to CD127 down-regulation, and CD25 up-regulation, on other subsets of CD4 + T cells following activation by cognate .In 2007, it was shown that murine Treg cells co-express the ectoenzymes CD39 and CD73 [10]. These ectonucleotidases work in concert to convert adenosine triphosphate (ATP), adenosine diphosphate and adenosine monophosphate to immunosuppressive adenosine, which appears to play a role in the suppressive repertoire of Treg cells [10]. Apart from contributing to adenosine produ...

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“…This supports previous studies where CD39, in combination with other Treg-cell surface markers, identified a population of human FOXP3 + suppressive Treg cells [11,14,43,44].…”

Section: Discussionsupporting

confidence: 79%

Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

et al. 2014

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“…Consistent with this, a recent study in juvenile RA patients reported a correlation between low CD73 expression and disease severity (7). In contrast, CD73 levels on jointinfiltrating immune cells have been shown to be decreased in some patients with juvenile RA (8).…”

supporting

confidence: 67%

“…It would be most interesting to assess whether deregulated CD73 expression and/or CD73 gene polymorphisms are associated with increased susceptibility to RA. In juvenile RA, for instance, where MTX displays considerable heterogeneity response rates, reduction of CD73 activity on mononuclear cells has been reported (8). Although correlation between CD73 polymorphism and autoimmunity has not been reported, a recent study by S. Robson and colleagues (16) revealed that polymorphisms in CD39 (ectonucleoside triphosphate diphosphohydrolase 1), a cell membranebound enzyme acting upstream of CD73 by converting ATP or ADP to AMP, is associated with increased susceptibility to inflammatory bowel disease in humans.…”

Section: Discussionmentioning

confidence: 99%

CD73 Plays a Protective Role in Collagen-Induced Arthritis

Chrobák

Charlebois

Rejtar

et al. 2015

The Journal of Immunology

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Rheumatoid arthritis (RA) is a chronic autoimmune disease with significant morbidity and mortality. Recent studies suggest that modulation of adenosine signaling, a potent immunosuppressive pathway, is a promising approach for treatment of RA. Extracellular adenosine can come from two sources: transport of intracellular adenosine and hydrolysis of extracellular adenine nucleotides by CD73. In this study, we investigated the susceptibility of CD73-deficient C57BL/6 mice to collagen-induced arthritis (CIA), a well-established mouse model of RA. Our data demonstrated that CD73-deficient mice are significantly more susceptible to CIA than wild-type mice. CD73 deficiency resulted in an increased production of proinflammatory cytokines in the joints, increased Th1 T cell responses, and increased joint destruction. Surprisingly, this was accompanied by delayed anticollagen IgG responses, suggesting defective isotype class switching in CD73-deficient mice. Using bone marrow chimera mice, we demonstrated that CD73 expression on nonhematopoietic cells, but not on hematopoietic cells, was important for protection from CIA. We further demonstrated that administration of a selective A2A adenosine receptor agonist to CD73-deficient mice resulted in arthritis incidence similar to wild-type mice in support of a protective role for A2A signaling. Taken together, our study identifies CD73 as an important regulator of CIA in mice. It also strengthens the notion that CD73-generated adenosine by nonhematopoietic cells plays a protective role in RA and suggests that strategies able to enhance CD73 activity or expression levels may be a valid therapeutic option.

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“…According to functional experiments performed by us (see Fig. S2 in the supplemental material) and others (38), the capability of Tregs to suppress proliferation seems to be confined exclusively to the CD4 ϩ , CD25 high , CD39 ϩ cell compartment. At the moment, it remains speculative whether CD39 acts as a switch for the suppressive function of Tregs.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Frequency and Phenotype of T Regulatory Cells in HIV Infection: CD39 Expression of FoxP3⁺T Regulatory Cells Correlates with Progressive Disease

Wiesch

Thomssen

Hartjen

et al. 2011

J Virol

162

184

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High Expression of the Ectonucleotidase CD39 on T Cells from the Inflamed Site Identifies Two Distinct Populations, One Regulatory and One Memory T Cell Population

Abstract: Material

Cited by 122 publications

References 49 publications

Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

CD73 Plays a Protective Role in Collagen-Induced Arthritis

Comprehensive Analysis of Frequency and Phenotype of T Regulatory Cells in HIV Infection: CD39 Expression of FoxP3⁺T Regulatory Cells Correlates with Progressive Disease

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High Expression of the Ectonucleotidase CD39 on T Cells from the Inflamed Site Identifies Two Distinct Populations, One Regulatory and One Memory T Cell Population

Abstract: Material

Cited by 122 publications

References 49 publications

Human antigen‐specific CD4+CD25+CD134+CD39+ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

Human antigen‐specific CD4+CD25+CD134+CD39+ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

CD73 Plays a Protective Role in Collagen-Induced Arthritis

Comprehensive Analysis of Frequency and Phenotype of T Regulatory Cells in HIV Infection: CD39 Expression of FoxP3+T Regulatory Cells Correlates with Progressive Disease

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Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

Human antigen‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

Comprehensive Analysis of Frequency and Phenotype of T Regulatory Cells in HIV Infection: CD39 Expression of FoxP3⁺T Regulatory Cells Correlates with Progressive Disease