Immune cell regulation by autocrine purinergic signalling

Abstract

Stimulation of almost all mammalian cell types leads to the release of cellular ATP and autocrine feedback through a diverse array of purinergic receptors. Depending on the types of purinergic receptors that are involved, autocrine signalling can promote or inhibit cell activation and fine-tune functional responses. Recent work has shown that autocrine signalling is an important checkpoint in immune cell activation and allows immune cells to adjust their functional responses based on the extracellular cues provided by their environment. This Review focuses on the roles of autocrine purinergic signalling in the regulation of both innate and adaptive immune responses and discusses the potential of targeting purinergic receptors for treating immune-mediated disease.

Figure 1. Components of autocrine purinergic signalling systems

The key elements of purinergic signalling include 1) ATP release from cells in response to activation of a cell surface receptor, for example by the opening of pannexin 1 (panx1) hemichannels in response to stimulation of formyl peptide receptor (FPR); 2) autocrine activation of P2 receptors; 3) hydrolysis of ATP and formation of adenosine by ectonucleotidases; 4) activation of P1 receptors; and 5) removal and recycling of adenosine (shown in blue). Autocrine purinergic signalling provides cells with quantitative cues (shown in red) that define how and to what extent to respond to specific qualitative cues they perceive via surface receptors that detect pathogens, antigens, danger signals, chemokines, and cytokines (shown in green). Autocrine purinergic signalling allows localized stimulation because purinergic signalling can be confined to specific regions and different spatiotemporal combinations of signalling components can be arranged to suite specific functional requirements. Moreover, these autocrine feedback processes can be influenced in paracrine fashion by purinergic receptor ligands that are generated by other cells or infected or damaged tissues.

Figure 2. Purinergic signal amplification regulates neutrophil chemotaxis

Neutrophil activation by bacterial formylated peptides such as fMLP requires stimulation of formyl peptide receptors (FPRs) that induce qualitative signals allowing the cells to recognize chemotactic cues (shown in green) that induce the release of ATP via pannexin 1, resulting in activation of adjacent P2Y2 receptors that provide signal amplification (shown in red) and facilitate gradients sensing (left), allowing cells to polarize within the chemotactic gradient filed (centre), which results in the translocation (shown in back) of pannexin 1, ENTPD1 (CD39), and A3 receptors to the leading edge. Accumulation of these purinergic signalling components facilitates focused ATP release and formation of adenosine at the leading edge, which leads to autocrine activation of A3 receptors that promote cell migration towards the source of fMLP (right). Unpublished work suggests that negative autocrine feedback via A2a adenosine receptors that block cell activation and remain uniformly distributed across the cell surface support chemotaxis by promote retraction of the receding edge (not depicted).

Figure 3. Regulation of phagocyte chemotaxis by autocrine and paracrine purinergic signalling mechanisms

Phagocytes such as neutrophils, monocytes, and macrophages require autocrine purinergic signalling and chemoattractants (danger signals) issuing from inflamed and infected sites to detect and migrate to such danger signals. Long-range signals such as fMLP, IL-8 and other chemoattractants promote the recruitment of phagocytes to affected tissues. ATP that is released from target cells is short lived and can thus only serves as a short-range signal that regulates the final encounter of phagocytes with the target cells. At this stage, ATP released from target cells entraps phagocytes by interfering with the autocrine purinergic signalling mechanisms (see Fig. 3), by promoting random migration, and by upregulating phagocytosis and other phagocyte killing mechanisms that result in effective clearance of target cells.

Figure 4. Purinergic signalling in T cell activation

Antigen recognition requires stimulation of the T cells via the immune synapse that froms between T cells and antigen-presenting cells (APCs). The immune synapse contains a large number of signalling molecules that are required for T cell activation, including TCRs, MHC molecules, costimulatory receptors and the purinergic signalling receptors P2X1, P2X4 and P2X7. In response to TCR and CD28 stimulation, pannexin 1 (panx1), P2X1 receptors, and P2X4 receptors translocate to the immune synapse. ATP released through pannexin 1 promotes autocrine signalling via the P2X receptors. Confinement of ATP in the immune synapse provides a powerful autocrine feedback mechanism that facilitates signal amplification required fro antigen recognition. P2 receptors and ATP release by APCs may play additional important roles in regulating the antigen recognition process.