In immunology, an immunological synapse (or immune synapse) is the interface between an antigen-presenting cell or target cell and a lymphocyte such as an effector T 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
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. Specific signalization pathways lead to polarization of the T-cell by orienting its centrosome toward the site of the immunological synapse. The symmetric centripetal actin flow lays at the basis of formation of the p-SNAP 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.
Immunological synapses were first discovered by Abraham Kupfer at the National Jewish Medical and Research Center in Denver. Their name was coined by Michael Dustin at NYU who studied them in further detail. Daniel M. Davis and Jack Strominger showed structured immune synapses for a different lymphocyte, the Natural Killer cell, and published this around the same time. Abraham Kupfer first presented his findings during one of the Keystone symposia in 1995, when he showed three-dimensional images of immune cells interacting with one another. Key molecules in the synapse are the T cell receptor and its counterpart the major histocompatibility complex (MHC). Also important are LFA-1, ICAM-1, CD28, and CD80/CD86.
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