Purinergic P2X4 Receptors and Mitochondrial ATP Production Regulate T Cell Migration

J Clin Invest. 2018 Aug 1;128(8):3583-3594. doi: 10.1172/JCI120972. Epub 2018 Jul 23.

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.

Keywords: Cell Biology; Mitochondria; T cells; Transplantation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / immunology*
  • Animals
  • Autocrine Communication / genetics
  • Autocrine Communication / immunology*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Movement / immunology*
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Jurkat Cells
  • Mice
  • Mice, Inbred BALB C
  • Mitochondria / genetics
  • Mitochondria / immunology*
  • Receptors, Purinergic P2X4 / genetics
  • Receptors, Purinergic P2X4 / immunology*

Substances

  • Receptors, Purinergic P2X4
  • Adenosine Triphosphate