In immunology, an immunological synapse (or immune synapse) is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T cell, B cell, or natural killer cell. The interface was originally named after the neuronal synapse, with which it shares the main structural pattern. An immunological synapse consists of molecules involved in T cell activation, which compose typical patterns—activation clusters. Immunological synapses are the subject of much ongoing research.
Structure and function The immune synapse is also known as the supramolecular activation cluster or SMAC. This structure is composed of concentric rings each containing segregated clusters of proteins—often referred to as the bull's-eye model of the immunological synapse:
c-SMAC (central-SMAC) composed of the θ isoform of protein kinase C, CD2, CD4, CD8, CD28, Lck, and Fyn. p-SMAC (peripheral-SMAC) within which the lymphocyte function-associated antigen-1 (LFA-1) and the cytoskeletal protein talin are clustered. d-SMAC (distal-SMAC) enriched in CD43 and CD45 molecules. New investigations, however, have shown that a "bull’s eye" is not present in all immunological synapses. For example, different patterns appear in the synapse between a T-cell and a dendritic cell. This complex as a whole is postulated to have several functions including but not limited to:
Regulation of lymphocyte activation Transfer of peptide-MHC complexes from APCs to lymphocytes Directing secretion of cytokines or lytic granules Recent research has proposed a striking parallel between the immunological synapse and the primary cilium based mainly on similar actin rearrangement, orientation of the centrosome towards the structure and involvement of similar transport molecules (such as IFT20, Rab8, Rab11). This structural and functional homology is the topic of ongoing research.
Formation The initial interaction occurs between LFA-1 present in the p-SMAC of a T-cell, and non-specific adhesion molecules (such as ICAM-1 or ICAM-2) on a target cell. When bound to a target cell, the T-cell can extend pseudopodia and scan the surface of target cell to find a specific peptide:MHC complex. The process of formation begins when the T-cell receptor (TCR) binds to the peptide:MHC complex on the antigen-presenting cell and initiates signaling activation through formation of microclusters/lipid rafts. Specific signaling pathways lead to polarization of the T-cell by orienting its centrosome toward the site of the immunological synapse. The symmetric centripetal actin flow is the basis of formation of the p-SMAC ring. The accumulation and polarization of actin is triggered by TCR/CD3 interactions with integrins and small GTPases (such as Rac1 or Cdc42). These interactions activate large multi-molecular complexes (containing WAVE (Scar), HSP300, ABL2, SRA1, and NAP1 and others) to associate with Arp2/3, which directly promotes actin polymerization. As actin is accumulated and reorganized, it promotes clustering of TCRs and integrins. The process thereby upregulates itself via positive feedback. Some parts of this process may differ in CD4+ and CD8+ cells. For example, synapse formation is quick in CD8+ T cells, because for CD8+ T cells it is fundamental to eliminate the pathogen quickly. In CD4+ T cells, however, the whole process of the immunological synapse formation can take up to 6 hours. In CD8+ T cells, the synapse formation leads to killing of the target cell via secretion of cytolytic enzymes. CD8+ T lymphocytes contain lytic granules – specialized secretory lysosomes filled with perforin, granzymes, lysosomal hydrolases (for example cathepsins B and D, β-hexosaminidase) and other cytolytic effector proteins. Once these proteins are delivered to the target cell, they induce its apoptosis. The effectivity of killing of the target cell depends on the strength of the TCR signal. Even after receiving weak or short-lived signals, the MTOC polarizes towards the immunological synapse, but in that case the lytic granules are not trafficked and therefore the killing effect is missing or poor.
The immunological synapse between different cell types More than just the junction between killer cells and infected or cancerous cells, the immunological synapse (IS) is the junction that forms between all immune cells when they communicate between each other, and their targets. Immune cells communicate to each other through the IS and specialized killing cells, such as Natural Killer cells (NK cells) and Cytotoxic T-lymphocytes (CTL's), form immunological synapses with the cells they kill. The IS is a dynamic location on immune cells that forms in response to a receptor signal and then functions to amplify that signal to either to induce apoptosis in targeted cells in the case of killer cells, or to transduce an activation or inhibition signal in the case of immune cells communicating to each other. An immune cell can be capable of forming a presynaptic IS where the immune cell is sending a signal, a postsynaptic IS where the cell is receiving a signal from another immune cell, or both. The following chart outlines the kinds and functions of IS that different immune cells can form. The IS itself is a highly organized structure consisting of various adhesion and receptor proteins that are arranged into specific activation clusters.
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