Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation
CD8+ T cells are a crucial part of the adaptive immune system, responsible for combating intracellular pathogens and tumor cells. The initial activation of T cells involves the formation of highly dynamic Ca2+ microdomains. Recently, purinergic signaling was shown to be involved in the formation of...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1258119/full |
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| author | Valerie J. Brock Niels Christian Lory Franziska Möckl Melina Birus Tobias Stähler Lena-Marie Woelk Lena-Marie Woelk Michelle Jaeckstein Joerg Heeren Friedrich Koch-Nolte Björn Rissiek Hans-Willi Mittrücker Andreas H. Guse René Werner René Werner Björn-Philipp Diercks |
| author_facet | Valerie J. Brock Niels Christian Lory Franziska Möckl Melina Birus Tobias Stähler Lena-Marie Woelk Lena-Marie Woelk Michelle Jaeckstein Joerg Heeren Friedrich Koch-Nolte Björn Rissiek Hans-Willi Mittrücker Andreas H. Guse René Werner René Werner Björn-Philipp Diercks |
| author_sort | Valerie J. Brock |
| collection | DOAJ |
| description | CD8+ T cells are a crucial part of the adaptive immune system, responsible for combating intracellular pathogens and tumor cells. The initial activation of T cells involves the formation of highly dynamic Ca2+ microdomains. Recently, purinergic signaling was shown to be involved in the formation of the initial Ca2+ microdomains in CD4+ T cells. In this study, the role of purinergic cation channels, particularly P2X4 and P2X7, in CD8+ T cell signaling from initial events to downstream responses was investigated, focusing on various aspects of T cell activation, including Ca2+ microdomains, global Ca2+ responses, NFAT-1 translocation, cytokine expression, and proliferation. While Ca2+ microdomain formation was significantly reduced in the first milliseconds to seconds in CD8+ T cells lacking P2X4 and P2X7 channels, global Ca2+ responses over minutes were comparable between wild-type (WT) and knockout cells. However, the onset velocity was reduced in P2X4-deficient cells, and P2X4, as well as P2X7-deficient cells, exhibited a delayed response to reach a certain level of free cytosolic Ca2+ concentration ([Ca2+]i). NFAT-1 translocation, a crucial transcription factor in T cell activation, was also impaired in CD8+ T cells lacking P2X4 and P2X7. In addition, the expression of IFN-γ, a major pro-inflammatory cytokine produced by activated CD8+ T cells, and Nur77, a negative regulator of T cell activation, was significantly reduced 18h post-stimulation in the knockout cells. In line, the proliferation of T cells after 3 days was also impaired in the absence of P2X4 and P2X7 channels. In summary, the study demonstrates that purinergic signaling through P2X4 and P2X7 enhances initial Ca2+ events during CD8+ T cell activation and plays a crucial role in regulating downstream responses, including NFAT-1 translocation, cytokine expression, and proliferation on multiple timescales. These findings suggest that targeting purinergic signaling pathways may offer potential therapeutic interventions. |
| first_indexed | 2024-03-08T00:51:12Z |
| format | Article |
| id | doaj.art-a2847c04e466468e97ea1424969ec6f1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T00:51:12Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a2847c04e466468e97ea1424969ec6f12024-02-15T04:52:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-02-011510.3389/fimmu.2024.12581191258119Time-resolved role of P2X4 and P2X7 during CD8+ T cell activationValerie J. Brock0Niels Christian Lory1Franziska Möckl2Melina Birus3Tobias Stähler4Lena-Marie Woelk5Lena-Marie Woelk6Michelle Jaeckstein7Joerg Heeren8Friedrich Koch-Nolte9Björn Rissiek10Hans-Willi Mittrücker11Andreas H. Guse12René Werner13René Werner14Björn-Philipp Diercks15The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyThe Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Applied Medical Informatics, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Computational Neuroscience, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyThe Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Applied Medical Informatics, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyDepartment of Computational Neuroscience, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyThe Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, GermanyCD8+ T cells are a crucial part of the adaptive immune system, responsible for combating intracellular pathogens and tumor cells. The initial activation of T cells involves the formation of highly dynamic Ca2+ microdomains. Recently, purinergic signaling was shown to be involved in the formation of the initial Ca2+ microdomains in CD4+ T cells. In this study, the role of purinergic cation channels, particularly P2X4 and P2X7, in CD8+ T cell signaling from initial events to downstream responses was investigated, focusing on various aspects of T cell activation, including Ca2+ microdomains, global Ca2+ responses, NFAT-1 translocation, cytokine expression, and proliferation. While Ca2+ microdomain formation was significantly reduced in the first milliseconds to seconds in CD8+ T cells lacking P2X4 and P2X7 channels, global Ca2+ responses over minutes were comparable between wild-type (WT) and knockout cells. However, the onset velocity was reduced in P2X4-deficient cells, and P2X4, as well as P2X7-deficient cells, exhibited a delayed response to reach a certain level of free cytosolic Ca2+ concentration ([Ca2+]i). NFAT-1 translocation, a crucial transcription factor in T cell activation, was also impaired in CD8+ T cells lacking P2X4 and P2X7. In addition, the expression of IFN-γ, a major pro-inflammatory cytokine produced by activated CD8+ T cells, and Nur77, a negative regulator of T cell activation, was significantly reduced 18h post-stimulation in the knockout cells. In line, the proliferation of T cells after 3 days was also impaired in the absence of P2X4 and P2X7 channels. In summary, the study demonstrates that purinergic signaling through P2X4 and P2X7 enhances initial Ca2+ events during CD8+ T cell activation and plays a crucial role in regulating downstream responses, including NFAT-1 translocation, cytokine expression, and proliferation on multiple timescales. These findings suggest that targeting purinergic signaling pathways may offer potential therapeutic interventions.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1258119/fullCD8 + T cellsCa2+ imagingactivationTCR stimulationCa2+ microdomainsNFAT |
| spellingShingle | Valerie J. Brock Niels Christian Lory Franziska Möckl Melina Birus Tobias Stähler Lena-Marie Woelk Lena-Marie Woelk Michelle Jaeckstein Joerg Heeren Friedrich Koch-Nolte Björn Rissiek Hans-Willi Mittrücker Andreas H. Guse René Werner René Werner Björn-Philipp Diercks Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation Frontiers in Immunology CD8 + T cells Ca2+ imaging activation TCR stimulation Ca2+ microdomains NFAT |
| title | Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation |
| title_full | Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation |
| title_fullStr | Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation |
| title_full_unstemmed | Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation |
| title_short | Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation |
| title_sort | time resolved role of p2x4 and p2x7 during cd8 t cell activation |
| topic | CD8 + T cells Ca2+ imaging activation TCR stimulation Ca2+ microdomains NFAT |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1258119/full |
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