The Immune Synapse

The term "immune synapse" (IS) was adopted from neuron physiology to represent a reciprocal attachment-activation-secretion system of intercellular communication occurring at specialized sites, between an immune effector cell and its target counterpart [35, 36]. The concept of immune synapse and its original definition are based on APC-lymphocyte interactions. In the broader context, IS may be generated by any specialized cell:cell interaction. CD4 and CD8 T cells, NK cells and B cells create immune synapses with antigen presenting cells, tumor targets, and with each other [37-42].

DC:T cell interaction and the subsequent transition of naïve CD8+ T cells into effector CTLs are but two steps towards the final goal which is target cell damage. It is surprising that little data has been provided thus far on the course of CTLs in peripheral tissues and their physical interaction with tumor cells, considering that this is their primary function. Due to paucity of information, the description of the IS is derived from models established with CTL:APC interactions. However, it is likely that these interactions follow a similar pattern when they occur between CTLs and tumor target, as will be described below.

In essence, IS refers to the redistribution of TCRs, their pMHC and co-receptors, with a reorientation of the cytoskeleton that polarizes and focuses release of effector molecules at the site of contact [37, 39, 40]. The immunological synapse serves several functions: (1) it increases T cell sensitivity to small amounts of antigen presented on the cell surface; (2) a stable attachment is created between the reacting cells; (3) effector molecules are directed and secreted to a specific site where their function is required; (4) the IS generates its own regulation and down-tuning.

Kupfer et al. [41] delineated the conformation of supramolecular activation clusters (SMAC) between APC and B cells, and later with T cells, in which CD4, LFA-1, IL-4, talin, and protein kinase C participate [41, 43]. A central domain of TCR cluster was defined as cSMAC, and a peripheral adhesive ring, enriched for the integrin LFA-1, as pSMAC [40, 44]. In addition to the TCR, cSMAC contains accessory molecules such as CD2 and CD28. These molecular clustering sites bring together ligands and receptors, thus increasing the likelihood of T cell activation. Stable binding at the IS creates tight, close contact between the interacting cells and is contributed by chemokines expressed on APCs. Chemokines are a group of highly charged small molecules easily adsorbed onto the cell surface. The increased adhesiveness of chemokine-expressing APCs facilitates binding of T cell receptors to their ligands most dominantly ICAM-1 [45]. This may be a first antigen independent step, that leads to an increased probability of TCR-pMHC encounter, and to enhanced T cell responsiveness to APC-generated peptides [46, 47]. Tumor cells may employ a similar mechanism. It was demonstrate that CD8+ T cells are directly activated by tumor cells depending on ICAM-1/LFA-1 interaction, as a CD80/CD86-CD28 independent costimulation [27]. Conversely, TCR triggering by pMHC results in denser display of LFA-1 and consequently stronger adhesion of T cell to APC [48]. As a result, both agonistic and "nule" peptides (peptides that bind to the MHC but do not activate TCR) binding to MHC lead to molecular clustering at the IS [49].

The reverse effect of chemokines, chemo-repulsion, was also shown, demonstrated in mice for CXCL12 expressed on tumor and its receptor CXCR4 on T cells [50].

The prime event that leads to the formation of IS is TCR recognition of its relevant peptide [44]. Using direct visualization, Davis et al. [51] found that a single pMHC complex was sufficient to arrest a CTL near an APC, to stimulate minimal calcium flux, and to induce transient immunological synapse formation. Stable immunological synapse formation required engagement with ten pMHC complexes [52]. In fact, possessing this extreme receptiveness to minute peptide load makes T cells a sensory organ [51]. Recently, it was proposed that the ability of T cells to augment TCR sensitivity to a given antigenic peptide is regulated by micro RNA (miRNA)181a, a 22 nt RNA piece that can repress multiple phosphatases and lead to reduction of the T cell receptor signaling threshold [53].

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