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Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration
Carola Ledderose, … , Gary A. Visner, Wolfgang G. Junger
Carola Ledderose, … , Gary A. Visner, Wolfgang G. Junger
Published June 12, 2018
Citation Information: J Clin Invest. 2018;128(8):3583-3594. https://doi.org/10.1172/JCI120972.
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Research Article Cell biology Article has an altmetric score of 4

Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration

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Abstract

T cells must migrate in order to encounter antigen-presenting cells (APCs) and to execute their varied functions in immune defense and inflammation. ATP release and autocrine signaling through purinergic receptors contribute to T cell activation at the immune synapse that T cells form with APCs. Here, we show that T cells also require ATP release and purinergic signaling for their migration to APCs. We found that the chemokine stromal-derived factor-1α (SDF-1α) triggered mitochondrial ATP production, rapid bursts of ATP release, and increased migration of primary human CD4+ T cells. This process depended on pannexin-1 ATP release channels and autocrine stimulation of P2X4 receptors. SDF-1α stimulation caused localized accumulation of mitochondria with P2X4 receptors near the front of cells, resulting in a feed-forward signaling mechanism that promotes cellular Ca2+ influx and sustains mitochondrial ATP synthesis at levels needed for pseudopod protrusion, T cell polarization, and cell migration. Inhibition of P2X4 receptors blocked the activation and migration of T cells in vitro. In a mouse lung transplant model, P2X4 receptor antagonist treatment prevented the recruitment of T cells into allograft tissue and the rejection of lung transplants. Our findings suggest that P2X4 receptors are therapeutic targets for immunomodulation in transplantation and inflammatory diseases.

Authors

Carola Ledderose, Kaifeng Liu, Yutaka Kondo, Christian J. Slubowski, Thomas Dertnig, Sara Denicoló, Mona Arbab, Johannes Hubner, Kirstin Konrad, Mahtab Fakhari, James A. Lederer, Simon C. Robson, Gary A. Visner, Wolfgang G. Junger

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Figure 6

P2X4 receptors promote mitochondrial activation and localized ATP release from migrating T cells.

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P2X4 receptors promote mitochondrial activation and localized ATP releas...
(A) Distribution of EGFP-tagged P2X4 receptors and mitochondria in unstimulated and SDF-1α–stimulated Jurkat cells. Histograms show the distribution of P2X4 receptor fluorescence along the cell axis as indicated (rectangle) and represent mean ± SD of 7 independent experiments. Arrow indicates direction of migration (see also Supplemental Video 7); ×100 objective. Scale bar, 10 μm. (B) Mitochondria are in the back of fast-moving cells and translocate to the front of cells probing their surroundings or engaging with other cells. CD4+ T lymphoblasts stained with MitoTracker Red CM-H2Xros (top row; ×63 objective) or with MitoTracker and 2-2Zn (bottom row; ×100 objective) are shown. Images are representative of 30 (top) or 15 (bottom row) experiments. Arrows in cells probing their environment indicate spots of increased mitochondrial activity (see also Supplemental Video 8). Scale bar, 10 μm. (C) Migration speed and mitochondrial localization were analyzed in 30-second increments in cells derived from 5 different experiments. The results shown comprise 73 single experiments. (D) Localization of mitochondria in the front half of fast-moving, probing, or interacting cells. Data represent mean ± SD of 30 cells, derived from 7 separate experiments; *P < 0.05 (Kruskal-Wallis test). (E) Representative images (left) and fluorescence intensity traces (right) of mitochondrial activity (MitoTracker Red CM-H2Xros) in CD4+ T lymphoblasts before and after P2X4 receptor inhibition (5-BDBD, 10 μM). Color coding was applied to demonstrate differences in mitochondrial activity. Right panel: Change in mitochondrial activity over time following treatment with 5-BDBD or culture medium (control). Data are representative of 20 cells; ×100 objective (see also Supplemental Video 9). Scale bar, 10 μm. (F) Averaged mitochondrial activity (mean ± SEM) of 22 (control), 20 (P2X4 inhibitor), or 11 (apyrase; 10 U/ml) cells analyzed in 2 (apyrase) or 3 individual experiments; *P < 0.05 (1-way ANOVA).

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