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The Dendritic Cell Side of the Immunological Synapse

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The Dendritic Cell Side of the Immunological Synapse BioMol Concepts 2016; 7(1): 17–28 Review Open Access Danielle R.J. Verboogen, Ilse Dingjan, Natalia H. Revelo, Linda J. Visser, Martin ter Beest and Geert van den Bogaart* The dendritic cell side of the immunological synapse DOI 10.1515/bmc-2015-0028 synapse mechanistically resemble that of lytic granule Received October 7, 2015; accepted November 18, 2015 release from T cells. Abstract: Immune responses are initiated by the interac- Keywords: antigen presentation; antigen-presenting tions between antigen-presenting cells (APCs), such as cell; dendritic cell; immunological synapse; membrane dendritic cells (DCs), with responder cells, such as T cells, trafficking; T cell. via a tight cellular contact interface called the immuno- logical synapse. The immunological synapse is a highly organized subcellular structure that provides a platform for the presentation of antigen in major histocompatibility Introduction class I and II complexes (MHC class I and II) on the surface Immunology is the ecology of human physiology. Where of the APC to receptors on the surface of the responder ecologists inventorise ecosystems, immunologists char- cells. In T cells, these contacts lead to highly polarized acterize the biodiversity of the lymphocytes that populate membrane trafficking that results in the local release of our body. Much like animals in a forest, immune cells lytic granules and in the delivery and recycling of T cell share a habitat and have symbiotic interactions with each receptors at the immunological synapse. Localized traf- other and with the other cells in our body. Especially inter- ficking also occurs at the APC side of the immunological esting is how immune cells respond to disturbances that synapse, especially in DCs where antigen loaded in MHC change these interactions such as infections or cancer (1). class I and II is presented and cytokines are released spe- Whereas these communications can occur over long dis- cifically at the synapse. Whereas the molecular mecha- tances by means of cytokines and chemokines, in clear nisms underlying polarized membrane trafficking at the analogy with the urine trails laid out by some animals T cell side of the immunological synapse are increasingly to attract or repel other animals, they can also occur via well understood, these are still very unclear at the APC direct cellular contact by means of immunological syn- side. In this review, we discuss the organization of the APC apses. Immunological synapses, a term derived from the side of the immunological synapse. We focus on the direc- morphologically similar neuronal synapse, are tight cel- tional trafficking and release of membrane vesicles carry- lular contact interfaces between antigen presenting cells ing MHC molecules and cytokines at the immunological (APCs) and effector cells [T cells or natural killer cells synapses of DCs. We hypothesize that the specific delivery (NKs)] (2, 3). of MHC and the release of cytokines at the immunological Immunological synapses are sites of polarized mem- brane transport where cytokines are locally released and membrane receptors are locally presented and recycled. *Corresponding author: Geert van den Bogaart, Department Whereas this process is now well studied in T cells and of Tumor Immunology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, NKs [reviewed in (4–7)], it is still less clear how local- 6525 GA Nijmegen, The Netherlands, ized membrane trafficking is regulated in APCs (8). In e-mail: [email protected]. this review we provide an overview on the molecular http://orcid.org/0000-0003-2180-6735 cascades that lead to polarized trafficking of cargo mol- Danielle R.J. Verboogen, Ilse Dingjan, Natalia H. Revelo, ecules to the immunological synapse, with an emphasis Linda J. Visser and Martin ter Beest: Department of Tumor Immunology, Radboud University Medical Center, Radboud on the trafficking events in dendritic cells (DCs). DCs are Institute for Molecular Life Sciences, Geert Grooteplein 28, professional antigen presenting cells that prime naïve 6525 GA Nijmegen, The Netherlands CD4+ helper and CD8+ killer T cells by means of an ©2016, Geert van den Bogaart et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. 18 D.R.J. Verboogen et al.: DC side of the immunological synapse immunological synapse (1, 9). We focus on the mecha- The classical ‘bulls eye’ immunological nisms underlying polarized trafficking of antigen-loaded synapse major histocompatibility complex (MHC) as well as of immunostimulatory cytokines from intracellular com- Our knowledge of the structure of the immunological partments to the immunological synapse, as this process synapse was propelled by the functional reconstitution of is of great importance for the initiation of antigen-specific immunological synapses with planar model membranes T cell responses. as surrogate APC [reviewed in ref. (6, 19, 20)]. With this technique the adhesion molecule ICAM-1 and MHC are functionally reconstituted in well-defined artificial bilay- ers and this suffices for synapse formation upon contact Structure of the immunological with T cells or NKs. Because the planar bilayer can be posi- synapse tioned directly on the surface of a microscope glass, this technique allows visualization of the synapse with total Not only DCs and T cells, but also other APCs, such as internal reflection fluorescence (TIRF) microscopy and B cells or infected cells, and other effector cells, such as other high resolution microscopy techniques. Synapses NKs, form immunological synapses for intercellular com- with APCs can also be visualized with high resolution munication as well as for the killing of (infected) target microscopy approaches, for instance by reorienting these cells (6, 10–12). There are thus many different types of synapses with a micromanipulator parallel to the focal immunological synapses and these can be functionally plane of the microscope (21). These and other techniques divided into two categories (13). The first category con- showed well-defined spatially segregated molecule clus- sists of the so-called primary synapses, which are the ters at the immunological synapse, and it is now well cell-cell contacts that result in initial activation of T cells established that the immunological synapse can organ- such as the synapses between DCs and T cells (8). In the ize in a ‘bulls eye’ arrangement called the monocentric T cell, the signals conferred at such an immunological synapse (19, 22). synapse can ultimately lead to their activation and clonal The monocentric synapse contains a distinct central expansion, depending on the type and activation state of region which is called the central supramolecular activa- the APC and on the efficiency of signal transduction (14, tion cluster (cSMAC) (22). The cSMAC was initially thought 15). The second category consists of the so-called second- to be the location of T cell signaling due to the presence ary synapses that result from interactions established of the T cell receptor (TCR) at the cSMAC. However, this after initial priming such as activated T cells delivering is no longer believed and the cSMAC is now considered stimulatory signals via, for example, CD40-CD40L inter- to be a site of signal termination and receptor recycling actions to B cells (1). This category also encompasses (23, 24). This conjecture is supported by the finding that the synapses formed between NKs or cytotoxic T cells dissociation of signaling molecules, such as Lck, ZAP-70 with their target APC where lytic granules are released and the adapter LAT, from the TCR microclusters occurs at to kill the APC (16). For both categories, the formation of the cSMAC (25). The peripheral SMAC (pSMAC) surrounds immunological synapses can trigger intracellular signal- the cSMAC and contains adhesion molecules, such as the ing cascades in both the APC and the T cell that lead to β2-integrin LFA-1 and ICAM-1, on the T cell and APC (19, reorganization of the cytoskeleton and rerouting of mem- 22, 26). These adhesion molecules provide a mechanical brane trafficking. scaffold for the immunological synapse and connect the Given the wide functional and structural variety of plasma membranes and cytoskeletons of the APC and T the different immunological synapses, their supramo- cell together (27). The pSMAC is in turn surrounded by a lecular organization is diverse and depends substan- more distally located SMAC (dSMAC) containing immune- tially on the interacting cell types, cellular activation inhibitory receptors such as CD43 and CD45 (28, 29). The states, as well as on antigen specificity involved (10, dSMAC also contains microdomains of T cell receptors 11, 14, 17). Accordingly, an immunological synapse can which (in contrast to cSMAC) are associated with signal- arrange in a well-structured ‘bulls eye’ monocentric ing molecules, such as Lck, ZAP-70 and LAT, indicating structure or can form more complex and heterogene- that receptor signaling primarily occurs in dSMAC (25, 30). ous polycentric arrangements. Furthermore, the time In the case of cytotoxic T cells and NK cells, the cSMAC duration of cellular engagement varies widely for differ- of the monocentric synapse contains a distinct and sep- ent synapses and can range from seconds up to several arated secretory region where release of lytic granules hours (13, 18). occurs (4, 31). D.R.J. Verboogen et al.: DC side of the immunological
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