Hormones and Immunity
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Regulation of T Helper Cell Function by Extracellular ATP

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Regulation of T Helper Cell Function by Extracellular ATP
Regulation T Helper Cell – Extracellular ATP

During immune responses a tight balance between proinflammatory and regulatory mechanisms is key in order to restore homeostasis and avoid excessive tissue damage. Among many factors modulating inflammation, extracellular nucleotides have emerged as constitutive signals of cell death alerting the immune system. Due to the ubiquitous expression of receptors for nucleotides and their metabolites, extracellular nucleotides, in particular ATP, exert a complex regulation of immune responses and depending on the context can activate or regulate immune responses.

Sources of extracellular ATP

Nucleotides are present at relatively high amounts in the cytoplasm of cells where their concentration ranges from 1–10 mM. In the extracellular space their concentration is considerably lower ranging between 1 and 10 nM. Due to the steep concentration gradient, their small size and their high mobility in the extracellular compartment, nucleotides can be rapidly released along with other cellular components following mechanical stress, cell damage or death. Increased nucleotide concentration in the extracellular space is therefore closely associated with tissue stress or damage [1-3]. However non-lytic nucleotide release may occur in many cell types under a variety of conditions. Activated platelets represent a relevant source of ATP released concomitantly with several inflammatory mediators during clot formation [4]. ATP is released from exercising skeletal muscle as well as from vascular endothelial cells and smooth muscle cells in conditions of increased blood flow or upon mechanical stimulus [5-8]. Moreover, ATP secretion from endothelial cells and leukocytes may be induced by pathogen-associated molecules such as LPS [9,10]. Finally commensal bacteria in the gut secrete discrete amounts of ATP that have been shown to exert important modulatory effects on immune responses [11].

Purinergic receptors

P2 receptors are a class of plasma membrane receptors expressed by virtually all cell types. Their activation elicits diverse responses depending on nucleotide concentration, cell type and receptors expressed. So far, two P2 receptor subfamilies have been described and named P2Y and P2X. Members of the two groups differ in protein structure, pharmacology and function [12-14]. P2Y receptors are seven membrane-spanning, G-protein- coupled receptors whose activation triggers generation of inositol 1,4,5-trisphosphate and release of Ca2+ from the intracellular stores [15]. Eight P2Y subtypes have been cloned so far and are named P2Y1,P2Y2, P2Y4, P2Y6, P2Y11, P2Y12,P2Y13, and P2Y14 [15,16]. Neurons, heart, skeletal muscle, platelets, liver and digestive tract express P2Y1 mRNA [15]. Stimulation of this subtype has been linked to platelet aggregation and nitric oxide (NO) release [17]. P2Y1 is potently activated by ADP. The P2Y2 receptor is expressed in skeletal muscle, heart, lung, spleen, placenta and kidney [15,18]. Its function has been linked to ion transport in epithelia [19]. P2Y2 is activated with similar efficiency by ATP and UTP. P2Y4 is present in the intestine, lung and placenta [15] . UTP is a potent agonist at P2Y4. Expression of P2Y6 has been found in many human tissues, including spleen, thymus, placenta, intestine, lung and brain [15,20,21]. UDP is very active at P2Y6. The P2Y11 subtype has been found in corneal epithelia, endothelial and pancreatic duct cells, promyelocytic HL-60 cells, dendritic cells and lymphocytes; ATP is the preferred physiological ligand at P2Y11 [22]. P2Y11 among P2 receptors has two unique characteristics: 1) its activation is associated with increased intracellular concentration of cyclic AMP [23-26] and 2) the human P2Y11 has no homologue in rodents and this has to be kept into consideration when comparing studies conducted in the mouse with those involving human cells.

CD34+ stem cells, mast cells, vascular smooth muscle cells and platelets express the P2Y12 subtype [27-29]. It is potently activated by ADP and linked to ADP-induced shape changes in platelets [30]. P2Y13 is expressed in bone marrow, spleen, liver, brain, airway epithelial cells, red blood cells, monocytes, dendritic and T cells [31-35]. P2Y13 has recently been linked to the regulation of hepatic high-density lipoprotein (HDL) endocytosis [36]. Its preferred agonist is ADP [37]. The recently identified P2Y14 subtype has been found in hematopoietic cells, monocyte-derived dendritic cells and human airway epithelial cells. The P2Y14 subtype responds to UDP-glucose and related sugar nucleotides [38-40].

Ligation of the agonist induces oligomerization and formation of homo- or in some cases hetero-multimer ion selective channels, being permeable to monovalent and divalent cations [41-43]. The P2X subunit is formed by an extracellular loop, two transmembrane domains and two (amino- and carboxyl-terminal) cytoplasmic domains. Seven P2X subtypes have been cloned so far (P2X1, P2X2, P2X3, P2X4,P2X5, P2X6, and P2X7). They were originally identified in mammalian neurons and smooth muscle cells, and subsequently also found in fibroblasts, lymphocytes, macrophages, and dendritic cells [14].

All P2X subtypes are activated by ATP. The P2X1 subtype is expressed by smooth muscle cells, megakariocytes, platelets, lymphocytes, dendritic cells, epithelial cells, ventricular myocardium, and neurons [44-47]. 20,30-(4-benzoyl)benzoyl-ATP (BzATP) and α,β-methylene ATP are good agonists at this subtype. P2X2 has different functional splice variants. 2-methyl-thio-ATP (2me-S-ATP) is a better agonist than ATP for this subtype. It is expressed in pancreatic cells and neurons, where along with P2X3,it is involved in nociceptive responses after nerve injury [48]. P2X3 receptor is expressed by neurons and its activation has been linked to nociceptive signaling [49,50]; mRNA expression of this subtype has also been found in keratinocytes, and CD43+ hematopoietic cell precursors [51]. P2X4 has been found in neurons, hematopoietic cell precursors, macrophages, monocyte-derived dendritic cells and fibroblasts, keratinocytes, and placenta [52-54]. P2X5 and P2X6 mRNAs have been detected in neurons, keratinocytes and thyrocytes [55-57]. The P2X7 receptor is expressed in macrophages, microglia, dendritic cells and placenta [16,58]. It is a non-desensitising receptor with the peculiar capacity to undergo a permeability transition from a cationic selective channel to a plasma membrane pore upon stimulation with high or pulsed ATP doses. BzATP is more potent than ATP at this subtype.

Role of ATP in Inflammation

Intracellular nucleotides like ATP, which functions in energy metabolism and which is normally stored in the cytosol, is released from a variety of cells under conditions of hypoxia, ischemia, inflammation or even mechanical stress [1,59,60]. Moreover ATP is “sensed” by leukocytes expressing a variety of P2 receptors. The ability of DCs to sense tissue stress is a cardinal point of the danger theory [61]. In this model, rather than be activated solely by the recognition of foreign pathogens, DCs react to the presence of environmental molecules associated with tissue stress, the so-called danger signals.

Danger signals can be classified into endogenous and exogenous. Endogenous danger signals can be further subdivided into constitutive (ATP, adenosine, some heat shock proteins) and inducible (type I interferons, some other heat shock proteins). Exogenous danger signals include microbial-associated molecules recognized by Toll-like receptors expressed on a variety of cells including DCs. The ability to recognize endogenous danger signals allows the immune system to discriminate between harmless (e.g., commensal flora at mucosal surfaces) and pathogenic organisms by assessing their effect (damage) on the host. In order to restore homeostasis, a timely termination of inflammatory processes is critical. Tissue damage might also be secondary to the intrinsic toxicity of sustained inflammation, which can ultimately be as harmful as the infection itself. Because of the number of receptor that can be stimulated by extracellular ATP and their wide distribution among different cell types, it is not surprising that the presence of ATP in the extracellular milieu can affect immune responses in various modes.

Among cells of the immune system a number of studies have described how extracellular ATP can modify dendritic cells biology. The effect of ATP on dendritic cell functions is rather complex. Several studies have described the proinflammatory action of ATP as activator of the inflammasome and inducer of TNF-α and IL-1β through the activation of the P2X7 receptor. In addition, recent evidences indicate that ATP plays a critical role in the induction of the proinflammatory Th17 lymphocyte subset. Conversely, ATP has been also shown to exert potent inhibitory effect on the production of TNF-α, IL-12, IL-1β and IL-6 stimulated by LPS in human dendritic cells and macrophages [62,63]. Several lines of evidence suggest that at least some of such immunosuppressive effects are mediated by the activation of the P2Y11 receptor and consequent increase of intracellular cAMP concentration.

Noteworthy, no homologues of the human P2Y11 receptor have been identified in rodents. In fact most studies conducted with murine cells converge in delineating a marked proinflammatory role for ATP, while in the human system both pro and anti-inflammatory effect have been documented.

As a consequence of impaired ability to produce IL-12 upon stimulation with LPS human monocyte derived DCs display reduced ability to induce Th1 differentiation of naïve T cells in vitro. In addition the expression of chemokines preferentially attracting Th1 cells such as CXCL10 and CCL5 is also severely reduced while the production of the Th2 attracting chemokines CCL22 and CCL17 is intact. Of note, CXCL10 is a relevant chemoattractant of NK cells that support Th1 differentiation by producing IFN-γ in the lymph node where DCs prime naïve T cells [64]. The production of IFN-γ by NK cells in the lymph node induces early intracellular events leading to differentiation of naïve T lymphocytes in Th1 cells such as activation of STAT-1 and expression of t-bet transcription factor.

Immature monocyte-derived DCs exposed to chronic stimulation with low micromolar concentrations of ATP but not UTP undergo partial membrane maturation and upregulate CD83, CD54, CD86 as well as the lymphoid chemokine receptor CCR7 conferring functional responsiveness to lymphoid chemokines such as CCL19 and CXCL12 [65,66]. Dendritic cells stimulated with ATP alone fail to produce detectable cytokines [66]. However, when DCs are stimulated with the prototypic stimulus bacterial endotoxin (LPS) in the presence of ATP, profound changes in the maturation program are induced.

While LPS-treated DCs produce high amounts of proinflammatory (IL-12, IL-23, TNF-α, IL-1, IL-6) and regulatory (IL-10 and IL-1 receptor antagonist) cytokines, when stimulated with LPS in the presence of low concentrations of ATP, DC production of IL-12p40, IL-12p70, TNF-α, and IL-1 is completely abrogated. Conversely, production of the regulatory cytokine IL-10 is unaffected and IL-1 receptor antagonist is increased. As a result of the blocked IL-12 production, DCs exposed to extracellular ATP have reduced ability to induce Th1 differentiation in vitro [66,67]. In addition, DC production of chemokines preferentially attracting Th1 polarised lymphocytes such as CXCL10 and CCL5 is also blocked, yet DCs still produce high amounts of the Th2-attracting chemokines CCL-22 and CCL-17 [65]. The lack of CXCL10 (a ligand for CXCR3) production might also impair DC contribution to the recruitment of NK cells into the lymph node, thus further favouring Th2 development. Most of the immune regulatory effects of extracellular ATP are also induced by increased levels of intracellular cyclic AMP, thus suggesting the involvement of the P2Y11 receptor, which has the unique (among P2 receptors) ability to stimulate adenylate cyclases. Figure 1 summarizes the cellular interplay leading to naïve T cell priming and polarization into Th1 lymphocytes and the impact of the elevation of cAMP on dendritic and NK cells.

Figures 1A and 1B – Effects of ATP increased intracellular concentration of cyclic AMP caused by P2Y11 triggering blocks cellular cross-talk leading to T helper 1 differentiation in the lymph node.

ATP T helper cells

Figure 1A. Dendritic cells migrating to lymph node from peripheral tissues produce chemokines able to recruit NK cells that, in turn secrete discrete amounts of IFN-γ. Interferon-γ stimulates STAT-1 activation and the expression of the transcription factor t-bet that is critical for cellular polarization toward the Th1 phenotype. In addition IFN-γ induces the expression of IL-12 receptor on naive T cell membrane. In such context IL-12 produced by DC is able to induce efficient differentiation of naive T cells into Th1 lymphocytes and along with TNF-α, stimulates, IFN-γ production by NK cells. Plasmacytoid DCs might reinforce both IL-12 and IFN-γ production through secretion of type I interferons.

ATP and T helper cells

Figure 1B. Elevated intracellular levels of cAMP inhibit Th1 differentiation by multiple means. cAMP potently downregulates expression of IL-12 [72], IL-12 receptor [73], type I interferon (data not shown) and CXCL10 [74].

Taking into account that Th2 lymphocytes are thought to have a considerably less self-harmful action than Th1 counterpart, the above mentioned evidences depict an overall antiinflammatorty action of extracellular ATP that might represent negative feedback signal to limit excessive Th1 responses in the context of tissue damage. However other evidences complicate this picture: 1) ATP effect on IL-12 production by DCs depends on the context: DC stimulated by TNF-α undergo maturation but are unable to produce IL-12. In this setting ATP enables IL-12 production by DCs thus favouring Th1 priming; 2) Th17 are characterized by the production of IL-17 and sustain mediate tissue damage in many chronic and autoimmune diseases, and recent evidences indicate that ATP secreted by commensal bacteria is required for differentiation of T helper 17 lymphocyte subset in the intestinal lamina propria [68]. In support of the role of ATP in fostering Th17 differentiation, is the observation that a subset of CD4+CD25+foxp3+ regulatory T cells exerts potent suppression of Th17 cells by depleting the surrounding microenvironment of ATP through the expression of CD39 ectonucleotidase [69]; 3) P2X7, the best characterized P2 receptor, is implicated in TNF-α production and inflammasome activation leading to IL-1β release.

Although the direct effect of extracellular ATP on the capacity of T lymphocytes to produce cytokines has not been extensively studied, it has been reported that stimulation with the non hydrolysable ATP analog ATP-γ-S directly inhibited IFN-γ production in T lymphocytes [70]. However extracellular ATP has been recently shown to be required for T lymphocyte production of various cytokines including IFN-γ[71], again pointing out the fact that the end result of extracellular ATP effect depends on a complex integration of signals generated through the activation of several P2 and P1 purinergic receptors.

Conclusion

Extracellular ATP can modulate the function of cells of the innate immune system as well as of T lymphocytes. While several data point out ATP as a signal alerting innate immune system to trigger inflammation and foster proinflammatory T helper cells development such as Th17 lymphocytes, other evidences suggest that ATP might represent a negative feedback signal to limit excessive inflammation sustained by IFN-γ acting directly on Th1 cells and indirectly on DCs and NK that are instrumental for Th1 development. Such composite picture arises from the complex interplay of several purinergic receptors simultaneously triggered by extracellular ATP and its metabolites. Moreover data coming from studies on murine cells are not completely superimposable to those performed on human cells because of the fact that the P2Y11 receptor mediating potent modulatory activity and expressed in human cells, is not present in rodents. Further studies addressing the distinct role of each P2 receptor are needed to better understand how ATP regulate inflammation modifying T cell function.

Abbreviations: Adenosine 5’-triphosphate, ATP; Adenosine 5’-diphosphate, ADP; Uridine 5’-triphosphate, UTP; cyclic adenosine monophosphate, cAMP; dendritic cell, DC; plasmacytoid dendritic cell, pDC; natural killer, NK; messenger RNA, mRNA; T helper, Th; chemokine (C-C motif) ligand, CCL; chemokine (C-C motif) receptor; CCR chemokine (C-X-C motif) receptor, CXCR; cluster of differentiation; CD; lipopolysaccharide, LPS; tumor necrosis factor, TNF; interleukin, IL; interferon, IFN; signal transducers and activators of transcription, STAT; forkhead box P3, foxp3.

Author(s) Affiliation

F Molinari, L Pontecorvo & A la Sala – IRCCS San Raffaele Pisana, Rome, Italy
A la Sala – San Raffaele Sulmona, Sulmona, Italy

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