(Journal of Leukocyte Biology. 2002;72:636-642.)
© 2002
by Society for Leukocyte Biology
Gap junctions and connexins: potential contributors to the immunological synapse
Ernesto Oviedo-Orta* and
W. Howard Evans
* Bristol Heart Institute, Bristol Royal Infirmary, United Kingdom; and
Department of Medical Biochemistry and Wales Heart Research Institute, University of Wales College of Medicine, Cardiff, United Kingdom
Correspondence: Ernesto Oviedo-Orta, Bristol Heart Institute, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol BS2 8HW, UK. E-mail: e.oviedo-orta{at}bristol.ac.uk
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ABSTRACT
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Gap junctional communication is a widespread mechanism for metabolic coupling of adjoining cells. In the immune system, evidence has built up showing that lymphocytes possess the protein building blocks of gap junctions, the connexins. The most widespread is connexin 43, but connexin 40 is also present in secondary lymphoid organs. Inhibitors of gap junctional communication, especially the highly specific connexin mimetic peptides, have been shown to decrease the secretion of immunoglobulins and cytokines by T and B lymphocyte cocultures, indicating that connexins may play a fundamental role in lymphocyte physiology. Traditionally, connexins function when assembled into gap junction-intercellular channels. However, the possibility is now arising that gap junction hemichannels, previously viewed as plasma membrane precursors of gap junctions, are also involved in the release from cells of small metabolites, e.g., adenosine 5'-triphosphate and nicotinamide adenine dinucleotide+, and this opens up a second, possible paracrine function for connexins detected in lymphocytes. The increasing structural and functional evidence points to a potential role that lymphocyte gap junctional intercellular communication may play within the complex signaling components of the immunological synapse.
Key Words: cytometry • antibodies • cell adhesion • inflammation • intercellular communication • immune response • peptides • flow
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INTRODUCTION
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Direct cell-cell interactions constitute a basic element of lymphocyte responsiveness and are therefore fundamental in the maintenance of homeostatic equilibrium against infections and in the preservation of self-tolerance [1
]. Such direct interactions occur at highly polarized plasma membrane microdomains found between lymphocytes and antigen-presenting cells (APC), which are characterized by the establishment of a dynamic supramolecular complex often called the immunological synapse [2
], consisting mainly of receptor-ligand pairs that guarantee, in a coordinated manner, effective lymphocyte stimulation and the development of specific effector functions. Within the immunological synapse, intercellular signaling is driven by antigen-dependent and antigen-independent complexes, which, acting in concert with intracellular signaling molecules, create a functional unit [2
, 3
]. Antigen-independent interactions not only provide cell-cell adhesion but also signaling pathways and links with the underlying cytoskeleton promoting rearrangements in the molecular composition of the synapse with specific, functional consequences [4
].
Evidence has built up that direct intercellular cross-talk via gap junction channels occurs in the haemopoietic and immune systems, implying important physiological consequences. Intercellular coupling of systemic or primary and secondary lymphoid lymphocyte conglomerates is increasingly appreciated as being enabled by gap junctions [5
, 6
]. These are ubiquitous macromolecular assemblies that permit direct intercellular transfer of ions and metabolites of approximately 1 kDa and are widely regarded as potential signaling conduits underpinning metabolic cross-talk and integration (Fig. 1
).
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Figure 1. Schematic representation of a model for a gap junction plaque based on X-ray diffraction and electron microscopy studies (modified from ref [7
]).
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Gap junction intercellular channels are constructed of a family of multispanning membrane proteins, the connexins [8
]. Nineteen mouse connexins and 20 human connexins have been studied [9
], and they range in size from 26 to 62 kD. Connexins have been identified in all vertebrate cell types, the exceptions being platelets, sperm, and skeletal muscle. A family of sequence, unrelated, tetraspanning membrane proteins called innexins appear to carry out equivalent communicative functions in invertebrates [10
]. Detailed topographical studies carried out with Cx26, 32, and 43 have shown them to traverse the membrane four times. Connexins have a short (
20 amino acid) cytoplasmic amino terminus and a highly variable (18 amino acids in Cx26, 156 amino acids in Cx43, and 275 amino acids in Cx57) cytoplasmic carboxyl terminus, the length of which is the major determinant of overall size. Two disulfide-linked and highly conserved loops, which attach the first to the second and the third to the fourth membrane spanning domains, project into the extracellular gap. An intracellular loop of variable sequence and length (for example, 35 amino acids in Cx32, 55 amino acids in Cx43, and 105 amino acids in Cx47) connects the second and third membrane spanning domains; this domain shows high sequence variation between connexins. Figure 2
shows a generalized topographical arrangement of interacting connexins in a cutout showing a basic gap junction unit and indicates some of the general functions attributed to the various protein domains pertaining mainly to Cx32 and Cx43, the most studied connexins. It is highly likely that all connexins and possibly also innexins are arranged in the membrane in the same manner. Although connexins share a common molecular design, it must be stressed that a range of connexin isoforms is expressed in tissues (as many as eight), for example, in the epidermis [11
]. During development, these varying ratios increasingly point to the conclusion that each connexin family member is probably functionally different; thus, the functions shown in Figure 2
apply mainly to Cx32 or Cx43.
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Figure 2. Fundamental unit of a gap junction two apposed connexins. The functions attributed to the various domains were deduced mainly from studies on Cx32 and Cx43. The four transmembrane domains of connexins are numbered. The sequences in the two extracellular loops used to design the two connexin mimetic peptides, GAP26 and GAP27, which inhibit interlymphocyte communication and functions, are indicated. Connexin mimetic peptides gain access to these loops via the intercellular gap; they may also interact directly with the loops in unapposed connexon hemichannels resident on cell surfaces. Shaded area indicates the gap junction channel connecting the cytoplasm of neighboring cells, and transmembrane domain 3 probably partially contributes to the channel wall.
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Connexins oligomerize in the membrane during transit along the secretory pathway, generating a connexon hexamer in which the subunits are arranged around a central pore. The extracellular domains in connexons, buried in the interacting plasma membranes, are crucial in the docking action, the final act in the creation of a gap junction intercellular channel. Progress in elucidating the molecular structure of Cx43, the most widely distributed tissue connexin and a key connexin in the cardiovascular and immune systems, has been reported [12
, 13
]. Two-dimensional crystals of recombinant Cx43 examined by electron cryocrystallography and three-dimensional mapping confirm the dodecameric arrangement of the 150 Å long intercellular channel constructed of two 65 Å channels traversing the two membranes and connected by a section of approximately 55 Å, which spans the extracellular gap [13
]. Studies with gap junctions constructed of Cx32 and Cx26 suggest a similar structure [14
]. Recent work indicates that Cx43 interacts via its cytoplasmic carboxyl tail with a number of accessory proteins, suggesting that the gap junction may exist as a part of a nexus structure that performs not only cell communication and adhesive functions but also interacts extensively with cytoplasmic proteins. Proteins interacting with Cx43 include tubulin, zona occludens 1, occludin, catenin, and CD38 [15
16
17
18
19
20
]. Cx43 has also been shown as being associated with important intracellular signaling kinases such as mitogen-activated protein kinase, v- and c-src, and protein kinase C [21
22
23
24
25
].
The assembly and breakdown of connexins into gap junction channels feature multiple intracellular pathways. Assembly of gap junction features three key steps: insertion and correct folding of connexins in membranes, connexin oligomerization to generate hexameric hemichannels, and their targeting to the plasma membrane. However, some connexins, e.g., Cx26, show nonclassical assembly behavior, as they insert into membranes (including plasma membrane) post-translationally [26
], and assembly into gap junctions does not require trafficking through the secretory pathway and is highly microtubule-dependent [27
]. Many cells express more than one connexin isoform with potential formation of homo- and heterotypic gap junctions from homo- and heteromeric connexon hemichannels, and these interactions involve strict connexin compatibility rules [8
]. For example, heteromeric hemichannels formed of Cx43 and Cx40, both ß connexins, have been demonstrated, but interactions between Cx43 and the 
connexin Cx26 do not occur. Connexins generally have a very rapid turnover with a half-life of 2–5 h [28
]. A direct, post-translational insertion of Cx26 into gap junctions also occurs [26
, 27
]. Although connexins are not glycosylated, they are extensively phosphorylated on the cytoplasmic carboxyl tail, a post-translational modification linked to channel gating but also likely to dictate connexin-accessory protein associations [29
]. Ubiquitination of connexins is a modification that points to intracellular breakdown in proteosomes and is one of a number of multiple degradation pathways that exist in cells [30
].
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IDENTIFICATION OF GAP JUNCTIONS IN THE IMMUNE SYSTEM
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The electrophysiological detection of low electrical resistance pathways between contacting cells is the historical gold standard implicating functional gap junctions as the cell contact organelles responsible for direct and rapid intercellular communication. Hulser and Peters [31
, 32
] studied lymphocyte aggregates induced by polyclonal stimulants such as phytohaemagglutinin and reported that the normally high ohmic resistance of the cell membrane was much reduced at these sites of cell contact. Similar studies by Oliveira-Castro et al. [33
] also identified and further highlighted the presence of low resistance electrical pathways connecting stimulated lymphocytes. Corroborating morphological input was obtained when gap junctions were identified by electron microscopy in lymphocytes [34
] and in macrophages [35
] as well as by freeze fracture in agglutinated rabbit lymphocytes from blood or spleen [36
]. Further evidence for the presence of gap junctions was obtained in undifferentiated granulocytes and epithelial cells during granulopoiesis [37
] and in lymphoreticular cells from rheumatoid synovial membranes [38
].
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GAP JUNCTIONS IN PRIMARY LYMPHOID ORGANS
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In primary lymphoid organs, lymphocytes, after differentiation from stem cells, acquire their repertoire of specific antigen receptors. More detailed reviews have been published discussing the expression and possible function of gap junctions in bone marrow stromal cells [5
, 39
40
41
].
Gap junctions, first identified in murine thymic lymphocytes [42
], were later extensively characterized in thymic epithelial cells and epithelial cell-thymocyte pairs, Cx43 was shown to be the major connexin, and gap junctional communication was blocked by the classical inhibitor octanol [43
]. It was suggested, for example, that gap junctional communication contributed to intrathymic neuroendocrine networks responsible for secretion of neuropeptides and vasoactive intestinal peptides [43
, 44
]. Stromal cells from murine bone marrow and fetal liver express Cx43, 45, 30.3, 31, and 31.1 and Cx43, Cx45, and Cx31, respectively [45
]. These studies also suggested that stromal cell Cx43 is involved in the supportive role played by haematopoietic progenitors and stem cells.
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GAP JUNCTIONS IN SECONDARY LYMPHOID ORGANS
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Lymphoid tissue provides an environment where lymphocytes interact with antigens and accessory cells, including a variety of dendritic and reticular cells, and a role for gap junctions has emerged where they may underpin lymphocyte trafficking, activation, and differentiation. Krenacs and Rosendaal and others [46
47
48
49
] surveyed the expression of several connexins in human lymphoid tissue and showed that Cx43 was the major, perhaps exclusive, gap junction protein. Importantly, it was also shown by these authors that Cx43 gap junctions couple follicular dendritic cells to each other and to B-lymphocytes. These studies involving immunocytochemical and dye transfer approaches further advanced the concept that gap junctions were likely to provide communication pathways linking up follicular dendritic meshworks and were thus positioned to play a role in synchronizing germinal center events such as during lymphocyte maturation in response to antigenic challenge. Cx43 was also detected in sinus lining cells in the deep cortex and medulla of the tonsils, suggesting that gap junctions were positioned to participate in antigen presentation and B cell activation [46
].
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SYSTEMIC LYMPHOCYTES EXPRESS FUNCTIONAL GAP JUNCTIONS
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The establishment of low-resistance channels in lymphocytes may constitute one of the early events in lymphocyte activation in response to mitogenic stimulation [31
, 32
], but these observations were neglected for many years in immunological circles. Investigators perceived the apparent, independent movement of these cells in the blood stream as behavior that would limit or impede any direct, cellular interactions and functional contact. However, spurred by the growing evidence discussed above of a role for gap junctions, especially in haematopoietic and lymphoid tissues, and increasing knowledge of dynamic interactions occurring between circulating cells and the vascular wall, the time was apposite to analyze in detail whether systemic lymphocytes possessed the molecular apparatus necessary for gap junctional communication and, if so, whether any physiological consequences of such interactions were evident. Analysis of expression of mRNA encoding Cx26, 32, 37, 40, 43, and 45 of T, B, and natural killer lymphocytes purified from blood of healthy volunteers and tonsils demonstrated that Cx43 was the major connexin in peripheral blood lymphocytes. In addition, T and B lymphocytes from secondary lymphoid organs expressed low amounts of Cx40. Flow cytometry using antibodies that detected epitopes on the extracellular loops [50
, 51
] showed Cx43 to be present at the cell surface, possibly in gap junction hemichannels. An in vitro approach also showed that a gap junction permeant dye, calcein, was transferred between lymphocytes, a process that was inhibited by two independent classes of gap junction inhibitors, connexin-mimetic peptides and 18--glycyrrhetinic acid [50
]. The connexin mimetics are well-characterized, nonpermeant short peptides that inhibit dye transfer and the calcium propagation between cells in a rapid and reversible manner [52
].
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FUNCTIONS OF GAP JUNCTIONS IN THE IMMUNE SYSTEM
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Despite the extensive characterization of gap junctions and connexins in the immune system, no specific functions were initially evident. However, exploitation of the connexin mimetic peptides as highly specific inhibitors of gap junctional communication has helped to clarify potential roles of gap junctions in lymphocyte interactions. These have raised new horizons of the potential functions of connexins in the immune system.
Exposure of lymphocytes for 10–50 h to connexin mimetic peptides designed from the two extracellular loops of Cx43 (Fig. 2) was shown to markedly reduce the secretion of immunoglobulin (Ig)M, IgG, and IgA in mixed cultures of purified human T and B lymphocytes [53
]. A less specific gap junction inhibitor, 18--glycyrrhetinic acid [52
], produced similar effects on Ig secretion. In addition, by using lymphocyte cocultures, it was demonstrated that a certain level of intercellular channel rectification was apparent between heterotypic and homotypic cultures of T and B cells, which suggested a role for lymphocyte gap junctions in the polarization of the immune response [53
]. Also, the gap junction inhibitors demonstrated complex temporal inhibitory effects on mRNAs encoding cytokines, especially interleukin-10 [53
].
A further distinction that might reflect important functional consequences in the signaling process between the different lymphocyte subpopulations was the finding that CD4+, CD8+, and CD19+ cells display a characteristic pattern of surface connexin protein expression under mitogenic stimulation, as revealed by fluorescent-activated cell sorter analysis using extracellular loop connexin antibodies [50
]. Whereas CD4+ and CD19+ lymphocytes followed the same dynamic pattern of membrane expression, CD8+ lymphocytes displayed no change in the surface pattern of connexin expression [50
].
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GAP JUNCTIONS AND INFLAMMATION
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With acceptance of functional roles for connexins and gap junctions in the immune system, it can be hypothesized that they are also implicated in inflammation. Admittedly, evidence for such roles is circumstantial, but several indirect findings indicate that connexins are likely to feature in inflammatory processes. Examples include peripheral nerve injury in which the recruitment of macrophages and fibroblast-like cells correlated with increased synthesis of Cx43 by these cells and a parallel increase in cytokine and growth factor synthesis by Schwann cells [54
55
56
]. Conversely, after subsidence of the inflammatory response, Cx43 levels drop, and other connexins appear [55
]. Increased Cx43 expression has been also noted in inflammatory kidney disease [57
, 58
].
The interaction of leukocytes with the vascular wall is an inflammatory event that underpins, among others, atherosclerotic plaque formation in which there is evidence of gap junctional involvement. The major connexins expressed in the vasculature are Cx43, Cx40, Cx45, and Cx37; the latter are often regarded as characteristic of endothelium. For example, vascular connexins are differentially expressed by atheroma-associated cells within lesions, suggesting a role for gap junctional communication during atherogenesis [59
]. Contraction and relaxation of arteries and the functional coupling of endothelial cells and smooth muscle cells are likely to be coordinated by direct communication across gap junctions [60
, 61
].
Interactions of lymphocytes with endothelium implicate a range of adhesion molecules and focal adhesion components, and during transmigration of lymphocytes across endothelium, it is likely that contact can elicit temporal gap junction formation, as connexins and probably connexon hemichannels are present in the plasma membranes of both cell types. In theory, homotypic and heterotypic junctions would be generated. Indeed, using in vitro model systems, a gap junction-mediated communication between cultured endothelial cells and lymphocytes has been demonstrated [62
, 63
]. As lymphocytes up-regulate Cx43 expression and gap junctional communication with polyclonal stimulants, especially following ischaemia-reperfusion injury [64
], the scene is set for a possible connexin-mediated interaction in inflammation in blood vessels. Although macrophages are usually the major cell type implicated in foam cell formation, recent work also points to the presence of Cx43 in these cells [65
66
67
]. As discussed below, the possible involvement of connexin hemichannels in nucleotide release adds a further dimension, as it introduces another extracellularly mediated mechanism of communication. On a broader front, studies in neural systems [68
] point to a role for gap junctions in inflammatory response in situations of oxidative stress and stroke, although currently, astrocyte and astrocyte-endothelial interactions are more likely to be implicated [69
]. Some genetically inherited disorders are now associated with connexin mutations, including Charcot-Marie-Tooth X-linked disease, nonsyndromic deafness, skin diseases, and cataract formation [70
, 71
].
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CONCLUDING REMARKS
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Given the wide distribution of connexins in vertebrates, it is, in retrospect, not surprising now that gap junctions have been found to be relatively abundant in extensively coupled tissues such as the haematopoietic system and the central and secondary lymphoid organs. Perhaps more surprising has been their detection in cells such as circulating lymphocytes and their association with functional subclasses of lymphocytes. It is tempting to suggest that they should be considered as fundamental constituents of the immunological synapse that underwrites much of the functions of T lymphocytes [72
]. This view is indirectly supported by results showing that blockage of T and B cell interaction led to a substantial drop in Ig secretion and cytokine synthesis [53
]. Clearly, knowledge of the nature substances transferred through lymphocyte gap junction channels would help to substantiate the above thesis. Conventionally, connexins are regarded as components of gap junction channels, bridging two cytoplasmic environments across contacting plasma membranes and thereby enabling cell coupling. However, studies mainly on intercellular Ca2+ wave propagation identify two routes [69
, 73
, 74
]. One route involves communication via gap junctions, and the other implicates gap junction hemichannels acting as vehicles for the release of adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate, and nicotinamide adenine dinucleotide (NAD)+ [73
, 75
76
77
78
79
80
] into the extracellular fluids. Both of these mechanisms, illustrated in Figure 3
, therefore implicate connexins. Knowledge of the roles of gap junction hemichannels is growing, and although they have been studied mainly in the intercellular propagation of Ca2+ waves, it is possible that they may also feature in signaling in interacting lymphocytes and between lymphocytes and the vascular wall. A new world of cell signaling, relevant to immunology, is on the horizon.
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Figure 3. Hypothetical scheme showing how connexins underwrite communication pathways regulating lymphocyte biology. Two pathways are shown: one classical, featuring direct communication across gap junction channels, and a second, extracellular paracrine pathway, involving release of ATP and NAD+ by connexon hemichannels. (A) Two lymphocytes (L) or a lymphocyte and an APC are shown to communicate in both directions by the above mechanisms. (B) A lymphocyte (L) transmigrating across an endothelial cell (E) monolayer of the vasculature [63
] communicates by both connexin-based modes with endothelial cells.
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Received March 7, 2002;
accepted May 2, 2002.
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