| First Author | Ledderose C | Year | 2018 |
| Journal | J Clin Invest | Volume | 128 |
| Issue | 8 | Pages | 3583-3594 |
| PubMed ID | 29894310 | Mgi Jnum | J:265440 |
| Mgi Id | MGI:6197639 | Doi | 10.1172/JCI120972 |
| Citation | Ledderose C, et al. (2018) Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J Clin Invest 128(8):3583-3594 |
| abstractText | 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-1alpha (SDF-1alpha) 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-1alpha 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. |
