Memory of Extracellular Adenosine A2A Purinergic Receptor-mediated Signaling in Murine T Cells

Koshiba, Masanori; Kojima, Hiroko; Huang, Shun; Apasov, Sergey; Sitkovsky, Michail V.

doi:10.1074/jbc.272.41.25881

Cited by 173 publications

(191 citation statements)

References 38 publications

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“…Moreover, given the fact that tissue inflammation/destruction is always accompanied by prolonged local hypoxia, our results also suggest that hypoxia/HIF-2a/ adora2a axis may serve as a molecular "brake" system to control undue inflammation through its effect on NKT cells. It was reported 27,28 that adora2a activation in T cells could inhibit their FasL expression and cytotoxicity. However, no reports correlated adora2a activation with FasL inhibition in NKT cells.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 To determine whether adora2a was behind FasL upregulation in HIF-2a 2/2 NKT cells and the role of HIF-2a in adora2a expression, WT and Mx1-HIF-2a 2/2 mice were placed in airtight chambers under normoxic (21% oxygen) or hypoxic conditions (10% oxygen). As shown in Figure 8, A and B, adora2a was constitutively expressed in thymocytes but not splenocytes.…”

Section: Compared With Wt Nkt Cells Adoptive Transfer Of Hif-2amentioning

confidence: 99%

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Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Zhang

Han

Dai

et al. 2016

Journal of the American Society of Nephrology

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Natural killer T (NKT) cells are the major early-acting immune cell type and fundamental immune modulators in ischemia-reperfusion injury (IRI). Because lymphocytes are exposed to various oxygen tensions under pathophysiologic conditions, we hypothesize that hypoxia-inducible factors (HIFs) have roles in NKT cell activation, and thus determine the final outcome of renal IRI. In this study, we used Lck-Cre transgenic mice to specifically disrupt HIF-2a in T/NKT cells and found that HIF-2a knockout led to upregulated Fas ligand expression on peripheral NKT cells, but not on conventional T cells. HIF-2a knockout promoted infiltration of NKT cells into ischemic kidneys and exacerbated IRI, which could be mitigated by in vivo NK1.1 + cell depletion or Fas ligand blockade.Compared with wild-type NKT cells, HIF-2a 2/2 NKT cells adoptively transferred to Rag1-knockout mice elicited more severe renal injury, and these mice were not protected by CGS21680, an adenosine A2A receptor agonist. Mechanistically, hypoxia-induced expression of adenosine A2A receptor in NKT cells and CGS21680-induced cAMP production in thymocytes were HIF-2a-dependent. Hydrogen peroxide-induced Fas ligand expression on thymic wild-type NKT cells was significantly attenuated by CGS21680 treatment, but this effect was lost in HIF-2a 2/2 NKT cells. Finally, CGS21680 and LPS, an inducer of HIF-2a in endothelium, synergistically reduced renal IRI substantially, but this effect was absent in Mx1-Cre-induced global HIF-2a-knockout mice. Taken together, our results reveal a hypoxia/HIF-2a/adenosine A2A receptor axis that restricts NKT cell activation when confronted with oxidative stress and thus protects against renal IRI.

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Section: Discussionmentioning

confidence: 99%

Section: Compared With Wt Nkt Cells Adoptive Transfer Of Hif-2amentioning

confidence: 99%

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Zhang

Han

Dai

et al. 2016

Journal of the American Society of Nephrology

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“…21 Previous studies by us and others have shown that low micromolar concentrations of adenosine interfere with the adhesion of mouse AK-T cells to tumor target cells, as well as compromising cytotoxic effector mechanisms that are dependent on granule exocytosis and Fas ligand expression. [22][23][24][25] In the present investigation, we demonstrate that adenosine, at concentrations typically present in the extracellular fluid of solid tumors, interferes with the induction of mouse AK-T cells and may, therefore, contribute to the resistance of solid tumors to immune attack by blocking the activation and expansion of cytotoxic effector cells at an early stage of the antitumor immune response.…”

mentioning

confidence: 99%

Adenosine acts through an A₃ receptor to prevent the induction of murine anti‐CD3‐activated killer T cells

Butler

Drapeau

Haeryfar

et al. 2002

Intl Journal of Cancer

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“…Thus, binding of adenosine to these receptors expressed on T cells causes suppression of T cell-mediated adaptive immune responses like release of various immunoregulatory cytokines (i.e., IL-2, TNF-α, and IFN-γ) without significantly affecting their expansion [157,158,240]. However, this impairment in effector T cell function remained maintained in these T cells even after the removal of A 2A adenosine receptor agonist, reflecting the generation T cell memory of the immunomodulatory action of adenosine as described earlier [239]. Adenosine-mediated inhibition of IL-2 in tumor microenvironment prevents clonal expansion of immunologically active antitumor T cells.…”

Section: Adenosine and T Cellsmentioning

confidence: 95%

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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Memory of Extracellular Adenosine A2A Purinergic Receptor-mediated Signaling in Murine T Cells

Cited by 173 publications

References 38 publications

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Adenosine acts through an A₃ receptor to prevent the induction of murine anti‐CD3‐activated killer T cells

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

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Memory of Extracellular Adenosine A2A Purinergic Receptor-mediated Signaling in Murine T Cells

Cited by 173 publications

References 38 publications

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Hypoxia-Inducible Factor-2α Limits Natural Killer T Cell Cytotoxicity in Renal Ischemia/Reperfusion Injury

Adenosine acts through an A3 receptor to prevent the induction of murine anti‐CD3‐activated killer T cells

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

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Adenosine acts through an A₃ receptor to prevent the induction of murine anti‐CD3‐activated killer T cells