Article

Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells

Department of Cardiovascular Physiology, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany.
AJP Cell Physiology (Impact Factor: 3.67). 05/2011; 301(2):C530-9. DOI: 10.1152/ajpcell.00385.2010
Source: PubMed

ABSTRACT CD73-derived adenosine acts as potent inhibitor of inflammation, and regulatory T cells (Treg) have been shown to express CD73 as a novel marker. This study explored the role of endogenously formed adenosine in modulating NF-κB activity and cytokine/chemokine release from murine Treg and effector T cells (Teff) including key enzymes/purinergic receptors of extracellular ATP catabolism. Stimulating murine splenocytes and CD4(+) T cells with anti-CD3/anti-CD28 significantly upregulated activated NF-κB in CD73(-/-) T cells (wild type: 4.36 ± 0.21; CD73(-/-): 6.58 ± 0.75; n = 4; P = 0.029). This was associated with an augmented release of proinflammatory cytokines IL-2, TNF-α, and IFN-γ. Similar changes were observed with the CD73 inhibitor APCP (50 μM) on NF-κB and IFN-γ in wild-type CD4(+) T-cells. Treatment of stimulated CD4(+) T-cells with adenosine (25 μM) potently reduced IFN-γ release which is mediated by adenosine A2a receptors (A2aR). AMP (50 μM) also reduced cytokine release which was not inhibited by APCP. In Teff, A2aR activation (CGS21680) potently inhibited the release of IL-1, IL-2, IL-3, IL-4, IL-12, IL-13, IFN-γ, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), CCL3, and CCL4. However, in Treg, CGS21680 did not alter cytokine/chemokine release. In summary, CD73-derived adenosine tonically inhibits active NF-κB in CD4(+) T-cells, thereby modulating the release of a broad spectrum of proinflammatory cytokines and chemokines. Downregulation of P2X7 and upregulation of CD73 in Treg after antigenic stimulation may be an important mechanism to maintain the ability of Treg to generate immunosuppressive adenosine.

0 Followers
 · 
102 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Data from animal models of MS suggest that GM-CSF(+)CD4(+)T cells are pathogenic cells. Therefore, GM-CSF production by CD4(+)T cells of MS patients and their susceptibility to regulatory mechanisms were investigated. Intracellular flowcytometry was performed to determine the GM-CSF(+)CD4(+)T cell fraction in PBMC and CSF of MS patients and controls. The effect of regulatory T cells (Tregs) on GM-CSF production by CD4(+)T cells was studied in MS patients using a proliferation-suppression assay. Finally, GM-CSF(+)CD4(+)T cell fraction and GM-CSF protein levels in supernatant were assessed in anti-CD3-stimulated CD4(+)T cell cultures derived from healthy controls and MS patients, in the presence or absence of the active vitamin D metabolite calcitriol. The GM-CSF(+)CD4(+)T cell fraction in the peripheral blood did not differ between controls and MS patients. This T cell population could also be detected in the CSF of both subjects with MS as well as subjects with another diagnosis. In the CSF, it comprised a significant fraction of the T cell population. Upon in vitro stimulation of PBMC with anti-CD3 antibody, no differences were observed in GM-CSF(+)CD4(+)T cell frequencies. GM-CSF secretion was susceptible to regulation by Treg and vitamin D. Suppression of GM-CSF secretion by vitamin D was reduced in MS patients. Our study showed no elevation in GM-CSF(+)CD4(+)T cell fractions in MS patients compared to controls. Furthermore, GM-CSF secretion was prone to regulation by Treg and vitamin D, the latter being less effective in MS patients. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Neuroimmunology 03/2015; 280:36-42. DOI:10.1016/j.jneuroim.2015.02.007 · 2.79 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 5´-nucleotidase/CD73 is a key enzyme in the regulation of purinergic signaling, hydrolyzing extracellular AMP to produce adenosine, which is critical in the blood vascular system and in immunosuppression. CD73 is expressed by both blood endothelial cells and lymphatic endothelial cells. Although the role of CD73 on blood endothelial cells in controlling vascular permeability and leukocyte trafficking has been studied, the role of lymphatic CD73 has thus far remained unknown. In this issue of European Journal of Immunology, Yegutkin et al. [Eur. J. Immunol. 2015. 45: XXXX-XXXX] compare CD73 activity in the endothelia of lymphatics and blood vessels and investigate the CD73+ lymphocyte subpopulations possibly involved in immunoregulation. This Commentary will discuss how the authors’ work sheds light on the differential use of CD73 by these two cell populations to control endothelial permeability and sprouting.This article is protected by copyright. All rights reserved
    European Journal of Immunology 01/2015; 45(2). DOI:10.1002/eji.201445400 · 4.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To highlight some of the recent developments in the novel field of immunometabolism and the therapeutic potential of the many regulatory components of this immunometabolic network for transplantation. In response to cytokines, changes in nutrients, and other alterations in the local milieu, immune cells are capable of changing their internal metabolic pathways to meet their energy demands. Recent studies demonstrate that activated T effectors (Th1 and Th17) are supported by aerobic glycolysis, whereas regulatory T cells and CD8 memory T cells favor fatty acid oxidation and lipid biosynthesis through mitochondrial oxidative phosphorylation. These bioenergetic processes are dependent upon the activation of metabolic sensors such as mammalian target of rapamycin and AMP-activated protein kinase, respectively, indicating that the cross-talk between immunity and metabolism can shape the fate and function of immune cells. Finally, exciting new studies suggest that differences in the bioenergetic mechanisms within the various immune subsets may selectively be exploited for regulating the immune responses. In this review, we will discuss the metabolic signatures adopted by various immune cells during tolerance versus immunity and the promising avenues that can be modulated by targeting metabolic pathways with either nutrition or pharmacological intervention for establishing long-term transplantation tolerance.
    Current Opinion in Organ Transplantation 02/2015; 20(1):21-8. DOI:10.1097/MOT.0000000000000149 · 2.38 Impact Factor