Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation
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Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation. / Brock, Valerie J; Lory, Niels Christian; Möckl, Franziska; Birus, Melina; Stähler, Tobias; Woelk, Lena-Marie; Jaeckstein, Michelle; Heeren, Joerg; Koch-Nolte, Friedrich; Rissiek, Björn; Mittrücker, Hans-Willi; Guse, Andreas H; Werner, René; Diercks, Björn-Philipp.
In: FRONT IMMUNOL, Vol. 15, 2024, p. 1258119.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation
AU - Brock, Valerie J
AU - Lory, Niels Christian
AU - Möckl, Franziska
AU - Birus, Melina
AU - Stähler, Tobias
AU - Woelk, Lena-Marie
AU - Jaeckstein, Michelle
AU - Heeren, Joerg
AU - Koch-Nolte, Friedrich
AU - Rissiek, Björn
AU - Mittrücker, Hans-Willi
AU - Guse, Andreas H
AU - Werner, René
AU - Diercks, Björn-Philipp
N1 - Copyright © 2024 Brock, Lory, Möckl, Birus, Stähler, Woelk, Jaeckstein, Heeren, Koch-Nolte, Rissiek, Mittrücker, Guse, Werner and Diercks.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.3389/fimmu.2024.1258119
DO - 10.3389/fimmu.2024.1258119
M3 - SCORING: Journal article
C2 - 38426095
VL - 15
SP - 1258119
JO - FRONT IMMUNOL
JF - FRONT IMMUNOL
SN - 1664-3224
ER -