Secretion of IL-2 and IFN-γ, But Not IL-4, by Antigen-Specific T Cells Requires Extracellular ATP

Langston, Heather P.; Ke, Yinghai; Gewirtz, Andrew T.; Dombrowski, Kenneth E.; Kapp, Judith A.

doi:10.4049/jimmunol.170.6.2962

Cited by 75 publications

(53 citation statements)

References 57 publications

(60 reference statements)

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“…[8][9][10][11][12][13] Stimulation of T cells by T-cell receptor (TCR) ligation, mechanical stimulation, membrane deformation, or osmotic stress induces the release of cellular ATP. 9,10,[13][14][15][16] T cells express the gap junction hemichannels pannexin-1, which can mediate ATP release and T-cell activation. 8,10 T-cell activation has been shown to involve P2X receptor subtypes.…”

Section: Introductionmentioning

confidence: 99%

Pannexin-1 hemichannel–mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse

Woehrle

Yip

Elkhal

et al. 2010

Blood

282

357

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Engagement of T cells with antigenpresenting cells requires T-cell receptor (TCR) stimulation at the immune synapse.We previously reported that TCR stimulation induces the release of cellular adenosine-5-triphosphate (ATP) that regulates T-cell activation. Here we tested the roles of pannexin-1 hemichannels, which have been implicated in ATP release, and of various P2X receptors, which serve as ATP-gated Ca 2؉ channels, in events that control T-cell activation. TCR stimulation results in the translocation of P2X1 and P2X4 receptors and pannexin-1 hemichannels to the immune synapse, while P2X7 receptors remain uniformly distributed on the cell surface. Removal of extracellular ATP or inhibition, mutation, or silencing of P2X1 and P2X4 receptors inhibits Ca 2؉ entry, nuclear factors of activated T cells (NFAT) activation, and induction of interleukin-2 synthesis. Inhibition of pannexin-1 hemichannels suppresses TCR-induced ATP release, Ca 2؉ entry, and T-cell activation. We conclude that pannexin-1 hemichannels and P2X1 and P2X4 receptors facilitate ATP release and autocrine feedback mechanisms that control Ca 2؉ entry and T-cell activation at the immune synapse. (Blood. 2010; 116(18):3475-3484) IntroductionT-cell activation requires a sustained elevation of intracellular Ca 2ϩ levels, which is accomplished by Ca 2ϩ entry through calcium release-activated calcium (CRAC) channels that are composed of stromal interaction molecule 1 (STIM1) and Orai1 proteins. [1][2][3] Both proteins translocate to the immune synapse upon T-cell activation, where they mediate localized influx of extracellular Ca 2ϩ . 4 Ca 2ϩ entry contributes to the activation of nuclear factors of activated T cells (NFATs) that induce interleukin-2 (IL-2) gene expression and subsequent signaling events that lead to T-cell proliferation. [5][6][7] Recent studies have shown that extracellular adenosine-5Ј-triphosphate (ATP) regulates T-cell activation. [8][9][10] T cells release ATP in a controlled manner, as do other leukocytes, thereby facilitating intercellular communication and autocrine feedback regulation of cell function. [8][9][10][11][12][13] Stimulation of T cells by T-cell receptor (TCR) ligation, mechanical stimulation, membrane deformation, or osmotic stress induces the release of cellular ATP. 9,10,[13][14][15][16] T cells express the gap junction hemichannels pannexin-1, which can mediate ATP release and T-cell activation. 8,10 T-cell activation has been shown to involve P2X receptor subtypes. 8,10 The 7 mammalian P2X receptor family members (P2X1-7) are ATPgated ion channels. 17,18 All these receptors, with the exception of P2X5, can facilitate entry of Ca 2ϩ in response to stimulation by extracellular ATP, [18][19][20] thus suggesting that P2X receptors regulate T-cell activation by mediating Ca 2ϩ entry.T-cell activation during antigen recognition requires the formation of an immune synapse between T cells and antigen-presenting cells. The immune synapse is a complex structure with a limited number of TCRs, implying that TCR stimu...

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Section: Introductionmentioning

confidence: 99%

Pannexin-1 hemichannel–mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse

Woehrle

Yip

Elkhal

et al. 2010

Blood

282

357

View full text Add to dashboard Cite

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“…[53][54][55][56] ATP also influences the specific immune response; in vitro stimulation of T cells with ATP induced T-cell activation and production of proinflammatory cytokines such as interleukin-2 and interferon-γ. 57 ATP stimulates the differentiation of naïve T cells to proinflammatory T helper 17 (Th17) cells, whereas in the absence of ATP, the development of regulatory T cells is supported. [58][59][60] CD39 is expressed by regulatory T cells and may be important for their regulatory and immunosuppressive action because, by hydrolyzing ATP and decreasing ATP concentration, it may induce differentiation of these regulatory T cells.…”

Section: Effects Of Atp and Adenosine On The Immune Responsementioning

confidence: 99%

Danger Signals From ATP and Adenosine in Pregnancy and Preeclampsia

et al. 2014

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“…Extracellular ATP and other nucleotides then signal through P2 receptors to modulate the immune and inflammatory response in a variety of cell types, including immune and nonimmune cells (17,20). In particular, extracellular ATP triggers the release of proinflammatory cytokines, including interleukin-1␤ (IL-1␤) (55) and IL-2 and gamma interferon (93). NTPDase expression modulates this response by controlling the level of extracellular nucleotides.…”

Section: Modulation Of the Host Inflammatory Responsementioning

confidence: 99%

“…Extracellular ATP and other nucleotides constitute potent "danger signals" for the host immune and inflammatory responses (17). ATP in particular can trigger the release of proinflammatory cytokines such as IL-1␤ through P2 receptor signaling (93). Extracellular ATP also activates dendritic cells and induces secretion of IL-12 (125).…”

Section: Interference With P2 Receptor Signaling By Parasitesmentioning

confidence: 99%

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Sansom

Robson

Hartland

2008

Microbiol Mol Biol Rev

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SUMMARYIn humans, purinergic signaling plays an important role in the modulation of immune responses through specific receptors that recognize nucleoside tri- and diphosphates as signaling molecules. Ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTPDases) have important roles in the regulation of purinergic signaling by controlling levels of extracellular nucleotides. This process is key to pathophysiological protective responses such as hemostasis and inflammation. Ecto-NTPDases are found in all higher eukaryotes, and recently it has become apparent that a number of important parasitic pathogens of humans express surface-located NTPDases that have been linked to virulence. For those parasites that are purine auxotrophs, these enzymes may play an important role in purine scavenging, although they may also influence the host response to infection. Although ecto-NTPDases are rare in bacteria, expression of a secreted NTPDase in Legionella pneumophila was recently described. This ecto-enzyme enhances intracellular growth of the bacterium and potentially affects virulence. This discovery represents an important advance in the understanding of the contribution of other microbial NTPDases to host-pathogen interactions. Here we review other progress made to date in the characterization of ecto-NTPDases from microbial pathogens, how they differ from mammalian enzymes, and their association with organism viability and virulence. In addition, we postulate how ecto-NTPDases may contribute to the host-pathogen interaction by reviewing the effect of selected microbial pathogens on purinergic signaling. Finally, we raise the possibility of targeting ecto-NTPDases in the development of novel anti-infective agents based on potential structural and clear enzymatic differences from the mammalian ecto-NTPDases.

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Secretion of IL-2 and IFN-γ, But Not IL-4, by Antigen-Specific T Cells Requires Extracellular ATP

Cited by 75 publications

References 57 publications

Pannexin-1 hemichannel–mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse

Pannexin-1 hemichannel–mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse

Danger Signals From ATP and Adenosine in Pregnancy and Preeclampsia

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

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