Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 8, Pages 3583-3594Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI120972
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Funding
- National Institutes of Health [GM-51477, GM-60475, GM-116162, AI-080582, T32 GM-103702]
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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-1 alpha (SDF-1 alpha) 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-1 alpha 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.
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