A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells

Zarek, Paul E.; Huang, Ching Tai; Lutz, Eric R.; Kowalski, Jeanne; Horton, Maureen R.; Linden, Joel; Drake, Charles G.; Powell, Jonathan D.

doi:10.1182/blood-2007-03-081646

Cited by 434 publications

(452 citation statements)

References 44 publications

(63 reference statements)

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“…This inhibitory effect appears to function via CD73 and A2A or A2B receptor. 41,42 This is different from the conventional view that Tregs suppress effector T cells in an IL-10-/or TGF-b-dependent manner. 25,43 Interestingly, a recent study reported that a subset of CRC-infiltrating CD4 C Tregs also express high CD39.…”

Section: Discussionmentioning

confidence: 54%

Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer

Cheng

et al. 2017

OncoImmunology

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Tumor microenvironment (TME) promotes immune suppression through recruiting and expanding suppressive immune cells such as regulatory T cells (Tregs) to facilitate cancer progression. In this study, we identify a novel CD39 C gdTreg in human colorectal cancer (CRC). CD39 C gdTregs are the predominant regulatory T cells and have more potent immunosuppressive activity than CD4 C or CD8 C Tregs via the adenosine-mediated pathway but independent of TGF-b or IL-10. They also secrete cytokines including IL-17A and GM-CSF, which may chemoattract myeloid-derived suppressive cells (MDSCs), thus establishing an immunosuppressive network. We further demonstrate that tumor-derived TGF-b1 induces CD39 C gdT cells from paired normal colon tissues to produce more adenosine and become potent immunosuppressive T cells. Moreover, CD39 C gdTreg infiltration is positively correlated with TNM stage and other unfavorable clinicopathological features, implicating that CD39 C gdTregs are one of the key players in establishment of immunosuppressive TME in human CRC that may be critical for tumor immunotherapy.

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Section: Discussionmentioning

confidence: 54%

Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer

Cheng

et al. 2017

OncoImmunology

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“…27 At the height of inflammation, the destruction of host tissue combined with damaged microcirculation and hypoxia leads to elevation of extracellular adenosine. 28 Animal models of asthma, 29 arthritis, 30 sepsis, 31 inflammatory bowel disease 32 and wound healing 33 have helped to elucidate the regulatory roles of adenosine in dictating the development and progression of disease. Adenosine potently inhibits a wide range of T-cell responses, including cell proliferation, 34 synthesis of IL-2 and proinflammatory cytokines, such as IFN-c and TNF-a, 35 and some of the earliest steps of T-cell activation, which were reported to be mediated mainly by the adenosine A 2A receptor.…”

Section: Pf Inhibits the Functions Of T Cells And Differentiation Of mentioning

confidence: 99%

Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

Liu

et al. 2011

Cell Mol Immunol

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Immunosuppressive mediators in tuberculosis pleurisy (pleural fluid (PF)) are associated with the course of disease, but they remain poorly defined. To study the local immune status of patients with tuberculosis pleurisy, we examined the effect of PF on the functions of T cells and the differentiation of Th1 cells. PF could inhibit the ability of T cells to produce cytokines. However, tumor-necrosis factor (TNF)-a derived from non-T cells was not impaired. Further analysis indicated that cell activation and cell cycle progression were also suppressed. Moreover, PF could inhibit Th1 cell differentiation. Importantly, we found that inhibitors of indoleamine 2,3-dioxygenase (IDO) and adenosine and neutralizing antibodies against IL-10 and transforming growth factor (TGF)-b could reverse cytokine production, suggesting that IDO, adenosine, IL-10 and Transforming growth factor-b1 in PF might take part in impairing T-cell functions. Taken together, our data demonstrate for the first time that several immunopathological factors participate in the downregulation of T-cell functions in local PF.

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“…ADO suppresses effector T-cell function through activation of adenosine receptor 2a (A2aR) and adenosine receptor 2b (A2bR) (15,16), which promote the blockade of cell proliferation, release of cytotoxic granules, expression of FasL, and proinflammatory cytokines secretion (17). Furthermore, activation of A2aR by ADO also enhances the generation of induced Tregs (iTregs) by inhibiting IL-6 expression and enhancing TGF-β secretion (18). In addition, ADO can also affect dendritic cell (DC) function, modulating their maturation and consequently driving them to a tolerogenic phenotype (19,20).…”

mentioning

confidence: 99%

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

Peres¹,

Liew

Talbot³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

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Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by joint destruction and severe morbidity. Methotrexate (MTX) is the standard first-line therapy of RA. However, about 40% of RA patients are unresponsive to MTX treatment. Regulatory T cells (Tregs, CD4 + CD25 + FoxP3 + ) are thought to play an important role in attenuating RA. To investigate the role of Tregs in MTX resistance, we recruited 122 RA patients (53 responsive, R-MTX; 69 unresponsive, UR-MTX) and 33 healthy controls. Three months after MTX treatment, R-MTX but not UR-MTX showed higher frequency of peripheral blood CD39 + CD4 + CD25 + FoxP3 + Tregs than the healthy controls. Tregs produce adenosine (ADO) through ATP degradation by sequential actions of two cell surface ectonucleotidases: CD39 and CD73. Tregs from UR-MTX expressed a lower density of CD39, produced less ADO, and had reduced suppressive activity than Tregs from R-MTX. In a prospective study, before MTX treatment, UR-MTX expressed a lower density of CD39 on Tregs than those of R-MTX or control (P < 0.01). In a murine model of arthritis, CD39 blockade reversed the antiarthritic effects of MTX treatment. Our results demonstrate that MTX unresponsiveness in RA is associated with low expression of CD39 on Tregs and the decreased suppressive activity of these cells through reduced ADO production. Our findings thus provide hitherto unrecognized mechanism of immune regulation in RA and on mode of action of MTX. Furthermore, our data suggest that low expression of CD39 on Tregs could be a noninvasive biomarker for identifying MTX-resistant RA patients.methotrexate | rheumatoid arthritis | adenosine | biomarker | ectonucleotidases

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A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells

Cited by 434 publications

References 44 publications

Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer

Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer

Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

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A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells

Cited by 434 publications

References 44 publications

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

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Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer

Tumor-infiltrating CD39⁺γδTregs are novel immunosuppressive T cells in human colorectal cancer