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

Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration

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 7

Inhibition of purinergic signaling prevents T cell recruitment in vivo.

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Inhibition of purinergic signaling prevents T cell recruitment in vivo. ...
(A and B) Recipient C57BL/6 mice were treated with the P2X4 inhibitor 5-BDBD or vehicle (DMSO) 24 hours before and immediately after transplantation of BALB/c lung allografts. (A) The number of CD4+ T cells infiltrating the lung allograft (left) and peak airway pressures (PAWP) in the allograft (right) were measured 24 hours after transplantation. For nontransplanted control and P2X4 inhibitor-treated group, n = 4; for DMSO-treated group, n = 6. Box plots: solid line indicates median, dotted line indicates mean; *P < 0.05, 1-way ANOVA (left) or unpaired 2-tailed Student’s t test (right). (B) Representative images of lung allografts 24 hours after transplantation. (C and D) In vitro proliferation of C57BL/6 CD4+ T cells (responders) cocultured in a mixed lymphocyte reaction with BALB/c splenocytes (stimulators) in the presence or absence of CCCP (1 μM), suramin (100 μM), NF279 (P2X1 antagonist; 20 μM), 5-BDBD (P2X4 antagonist; 20 μM), or A438079 (P2X7 antagonist; 20 μM) for 4 days. Representative dot plots (C) and averaged (mean ± SD) results (D) of 3 separate experiments are shown; *P < 0.05 vs. control (1-way ANOVA). (E) Purinergic regulation of T cell migration by P2X4 receptors. Chemokine receptors (e.g., CXCR4) trigger the production of ATP by mitochondria, ATP release through PANX1 channels, and autocrine stimulation of P2X4 receptors that facilitate Ca2+ influx, sustain mitochondrial ATP production, and promote pseudopod protrusion at the front of cells.