T Regulatory and Primed Uncommitted CD4 T Cells Express CD73, Which Suppresses Effector CD4 T Cells by Converting 5′-Adenosine Monophosphate to Adenosine

Kobie, James J.; Shah, Pranav R.; Li, Yang; Rebhahn, Jonathan; Fowell, Deborah J.; Mosmann, Tim R.

doi:10.4049/jimmunol.177.10.6780

Cited by 386 publications

(344 citation statements)

References 60 publications

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“…One of the suppressive mechanisms attributed to Treg cells is metabolic disruption, ascribed in part to the expression of CD39 and CD73 [11,59,60]. These ectonucleotidases act in concert to generate to hydrolyze ATP and ADP to adenosine.…”

Section: Discussionmentioning

confidence: 99%

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

et al. 2014

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CD4 + CD25 + Foxp3 + regulatory T (Treg) cells mediate immunological self-tolerance and suppress immune responses. Retinoic acid (RA), a natural metabolite of vitamin A, has been reported to enhance the differentiation of Treg cells in the presence of TGF-β. In this study, we show that the co-culture of naive T cells from C57BL/6 mice with allogeneic antigen-presenting cells (APCs) from BALB/c mice in the presence of TGF-β, RA, and IL-2 resulted in a striking enrichment of Foxp3 + T cells. These RA in vitro-induced regulatory T (RA-iTreg) cells did not secrete Th1-, Th2-, or Th17-related cytokines, showed a nonbiased homing potential, and expressed several cell surface molecules related to Treg-cell suppressive potential. Accordingly, these RA-iTreg cells suppressed T-cell proliferation and inhibited cytokine production by T cells in in vitro assays. Moreover, following adoptive transfer, RA-iTreg cells maintained Foxp3 expression and their suppressive capacity. Finally, RA-iTreg cells showed alloantigen-specific immunosuppressive capacity in a skin allograft model in immunodeficient mice. Altogether, these data indicate that functional and stable allogeneic-specific Treg cells may be generated using TGF-β, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation. Keywords: Allogeneic regulatory T cells r Homing r Retinoic acid r Tolerance r TransplantationAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionRegulatory T (Treg) cells are responsible for inducing and maintaining peripheral tolerance [1]. Treg cells are classified into two Correspondence: Dr. Daniela Sauma e-mail: dsauma@u.uchile.cl major subpopulations: thymus-derived Treg cells, which are generated in the thymus and circulate in the periphery as functional mature Treg cells [2][3][4], and peripherally derived Treg cells, which are generated in the periphery from CD4 + CD25 − naive * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 452-463 Immunomodulation 453T cells [5][6][7]. Treg cells target effector T cells and dendritic cells (DCs) by modulating their maturation and function through several mechanisms that suppress immune responses [8][9][10]; these include secretion of inhibitory cytokines (IL-10, IL-35, and TGF-β), granzyme/perforin-dependent mediated cytolysis, metabolic disruption [11][12][13][14][15], and the expression of LAG3 and CTLA4, which alter DC function [16,17]. In addition to the aforementioned mechanisms, Treg-cell suppressive capacity is dependent on Treg-cell migration and retention in the microenvironment where regulation is required. Differential expression patterns of chemokine receptors (such as CCR4, CCR5, and CCR9), integrins (α4β7), and selectins (CD62L) contribute to selective retention and trafficking of Treg cells and allow their appropriate localization during ...

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Section: Discussionmentioning

confidence: 99%

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

et al. 2014

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“…Tregs reduce eosinophil infiltration, Th2 cytokine production, and airway hyperreactivity (reviewed in [88,97]). ATP-degrading enzymes (CD39 and CD73) highly expressed on the membrane on Tregs are recognized recently as their activation markers [98,99]. Tregs exert immune suppression by increasing the concentration of intracellular cAMP in target cells [98].…”

Section: Purinergic Signaling In Allergic Airway Inflammation: Focus mentioning

confidence: 99%

P2 receptor-mediated signaling in mast cell biology

Bulanova

Bulfone–Paus∥

2009

Purinergic Signalling

101

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Mast cells are widely recognized as effector cells of allergic inflammatory reactions. They contribute to the pathogenesis of different chronic inflammatory diseases, wound healing, fibrosis, thrombosis/fibrinolysis, and antitumor immune responses. In this paper, we summarized the role of P2X and P2Y receptors in mast cell activation and effector functions. Mast cells are an abundant source of ATP which is stored in their granules and secreted upon activation. We discuss the contribution of mast cells to the extracellular ATP release and to the maintenance of extracellular nucleotides pool. Recent publications highlight the importance of purinergic signaling for the pathogenesis of chronic airway inflammation. Therefore, the role of ATP and P2 receptors in allergic inflammation with focus on mast cells was analyzed. Finally, ATP functions as mast cell autocrine/paracrine factor and as messenger in intercellular communication between mast cells, nerves, and glia in the central nervous system.

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“…Adenosine binding to A 2A R expressed by T cells suppresses their immunostimulatory activity. Kobie et al (2006) have shown that these FoxP3 + CD25 + CD4 + T regs express an extracellular 5′ectonucleotidase (CD73), which converts extracellular 5′-AMP to adenosine and suppresses T cell activity via binding to A 2A receptors on T cells [163]. have shown that FoxP3 + CD25 + CD4 + T regs also express CD39 ecto-ATPase/ADPase and CD73 ecto-5′nucleotidase, which shows involvement of these T regs in synthesis of extracellular adenosine [164].…”

Section: Adenosine and T Cellsmentioning

confidence: 99%

“…Primed uncommitted CD4 + T precursor Th (Thpp) cells and FoxP3 + CD25 + CD4 + T regs , produce immunosuppressive extracellular adenosine as both these cell types express CD73 (5′-ectonucleotidase), which has the potential to convert 5′adenosine monophosphate (5′-AMP) to adenosine [163]. Adenosine binding to A 2A R expressed by T cells suppresses their immunostimulatory activity.…”

Section: Adenosine and T Cellsmentioning

confidence: 99%

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

Kumar

2012

Purinergic Signalling

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Cancer is a chronic disease and its pathogenesis is well correlated with infection and inflammation. Adenosine is a purine nucleoside, which is produced under metabolic stress like hypoxic conditions. Acute or chronic inflammatory conditions lead to the release of precursor adenine nucleotides (adenosine triphosphate (ATP), adenosien diphosphate (ADP) and adenosine monophosphate (AMP)) from cells, which are extracellularly catabolized into adenosine by extracellular ectonucleotidases, i.e., CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. It is now well-known that adenosine is secreted by cancer as well as immune cells during tumor pathogenesis under metabolic stress or hypoxia. Once adenosine is released into the extracellular environment, it exerts various immunomodulatory effects via adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) expressed on various immune cells (i.e., macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), T cells, regulatory T cell (T regs ), etc.), which play very important roles in the pathogenesis of cancer. This review is intended to summarize the role of inflammation and adenosine in the immunopathogenesis of tumor along with regulation of tumor-specific immune response and its modulation as an adjunct approach to tumor immunotherapy.

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T Regulatory and Primed Uncommitted CD4 T Cells Express CD73, Which Suppresses Effector CD4 T Cells by Converting 5′-Adenosine Monophosphate to Adenosine

Cited by 386 publications

References 60 publications

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

P2 receptor-mediated signaling in mast cell biology

Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?

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