High Sensitivity of Intestinal CD8+ T Cells to Nucleotides Indicates P2X7 as a Regulator for Intestinal T Cell Responses

Heiß, Kirsten; Jänner, Nathalie; Mähnß, Birgit; Schumacher, Valéa; Koch-Nolte, Friedrich; Haag, Friedrich; Mittrücker, Hans‐Willi

doi:10.4049/jimmunol.181.6.3861

Cited by 49 publications

(50 citation statements)

References 47 publications

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“…In this model, T cells from P2X7-deficient mice proliferated more vigorously in response to antigen stimulation [32]. Furthermore, P2X7-deficient mice infected with L. monocytogenes exhibit higher frequencies of IFNγ + CD8 + T cells [33]. In accordance with these reports, we also observed a higher proliferation of CD4 + and CD8 + effector T cells and increased IFN-γ levels in paws from infected P2X7 KO mice.…”

Section: Discussionsupporting

confidence: 80%

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

Figliuolo

Chaves

Savio

et al. 2016

Purinergic Signalling

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Leishmania amazonensis is the etiological agent of diffuse cutaneous leishmaniasis. The immunopathology of leishmaniasis caused by L. amazonensis infection is dependent on the pathogenic role of effector CD4 + T cells. Purinergic signalling has been implicated in resistance to infection by different intracellular parasites. In this study, we evaluated the role of the P2X7 receptor in modulating the immune response and susceptibility to infection by L. amazonensis. We found that P2X7-deficient mice are more susceptible to L. amazonensis infection than wild-type (WT) mice. P2X7 deletion resulted in increased lesion size and parasite load. Our histological analysis showed an increase in cell infiltration in infected footpads of P2X7-deficient mice. Analysis of the cytokine profile in footpad homogenates showed increased levels of IFN-γ and decreased TGF-β production in P2X7-deficient mice, suggesting an exaggerated pro-inflammatory response. In addition, we observed that CD4 + and CD8 + T cells from infected P2X7-deficient mice exhibit a higher proliferative capacity than infected WT mice. These data suggest that P2X7 receptor plays a key role in parasite control by regulating T effector cells and inflammation during L. amazonensis infection.

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Section: Discussionsupporting

confidence: 80%

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

Figliuolo

Chaves

Savio

et al. 2016

Purinergic Signalling

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“…ATP, especially, is often stored and released in the co-presence of NAD+ [85,103]. For a long time, extracellular NAD+ has been addressed as a key signal of cell lysis with potent activation properties on several immune system cells [104][105][106] and as an inducer of intracellular calcium signals [107]. Its regulated co-storage and co-release with ATP lets us propose a more refined role in purinergic signaling, and ATP and NAD+, especially, appear to show synergistic activity by activation of several members of the purinergic receptor family, such as P2X7 and P2Y [108].…”

Section: Atp Storagementioning

confidence: 99%

ATP synthesis and storage

Bonora

Patergnani

Rimessi

et al. 2012

Purinergic Signalling

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Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge about this purine nucleotide has been greatly expanded. Many aspects of cell metabolism revolve around ATP production and consumption. It is important to understand the concepts of glucose and oxygen consumption in aerobic and anaerobic life and to link bioenergetics with the vast amount of reactions occurring within cells. ATP is universally seen as the energy exchange factor that connects anabolism and catabolism but also fuels processes such as motile contraction, phosphorylations, and active transport. It is also a signalling molecule in the purinergic signalling mechanisms. In this review, we will discuss all the main mechanisms of ATP production linked to ADP phosphorylation as well the regulation of these mechanisms during stress conditions and in connection with calcium signalling events. Recent advances regarding ATP storage and its special significance for purinergic signalling will also be reviewed.

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“…Only P2X 7 receptors are to date established as having physiological roles in inflammation, mostly via a rapid activation of caspase-1 with subsequent release of the proinflammatory cytokine IL-1␤ from activated macrophages and microglia (15,16). P2X 7 is also an important modulator of T cell functions (17)(18)(19)(20).…”

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confidence: 99%

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

Lecut

Frederix

Johnson

et al. 2009

The Journal of Immunology

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ATP, released at the leading edge of migrating neutrophils, amplifies chemotactic signals. The aim of our study was to investigate whether neutrophils express ATP-gated P2X1 ion channels and whether these channels could play a role in chemotaxis. Whole-cell patch clamp experiments showed rapidly desensitizing currents in both human and mouse neutrophils stimulated with P2X1 agonists, αβ-methylene ATP (αβMeATP) and βγMeATP. These currents were strongly impaired or absent in neutrophils from P2X1−/− mice. In Boyden chamber assays, αβMeATP provoked chemokinesis and enhanced formylated peptide- and IL-8-induced chemotaxis of human neutrophils. This agonist similarly increased W-peptide-induced chemotaxis of wild-type mouse neutrophils, whereas it had no effect on P2X1−/− neutrophils. In human as in mouse neutrophils, αβMeATP selectively activated the small RhoGTPase RhoA that caused reversible myosin L chain phosphorylation. Moreover, the αβMeATP-elicited neutrophil movements were prevented by the two Rho kinase inhibitors, Y27632 and H1152. In a gradient of W-peptide, P2X1−/− neutrophils migrated with reduced speed and displayed impaired trailing edge retraction. Finally, neutrophil recruitment in mouse peritoneum upon Escherichia coli injection was enhanced in wild-type mice treated with αβMeATP, whereas it was significantly impaired in the P2X1−/− mice. Thus, activation of P2X1 ion channels by ATP promotes neutrophil chemotaxis, a process involving Rho kinase-dependent actomyosin-mediated contraction at the cell rear. These ion channels may therefore play a significant role in host defense and inflammation.

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High Sensitivity of Intestinal CD8+ T Cells to Nucleotides Indicates P2X7 as a Regulator for Intestinal T Cell Responses

Cited by 49 publications

References 47 publications

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

ATP synthesis and storage

P2X1 Ion Channels Promote Neutrophil Chemotaxis through Rho Kinase Activation

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