In
immunology
Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
, an immunological synapse (or immune synapse) is the interface between an
antigen-presenting cell or target cell and a
lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
such as a
T/B cell or
Natural Killer cell
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...
. 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
In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
,
CD2
CD2 (cluster of differentiation 2) is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells.
It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette rece ...
,
CD4,
CD8
CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...
,
CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...
,
Lck
Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
, and
Fyn
Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
.
* p-SMAC (peripheral-SMAC) within which the lymphocyte function-associated antigen-1 (
LFA-1 Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates ...
) and the cytoskeletal protein
talin Talin may refer to:
Places
* Talin, Armenia, a city
* Tálín, a municipality and village in the Czech Republic
*Tallinn, capital of Estonia
* Talin, Iran, a village in West Azerbaijan Province
*Talin, Syria, a village in Tartus Governorate
Other
...
are clustered.
* d-SMAC (distal-SMAC) enriched in
CD43
Leukosialin also known as sialophorin or CD43 (cluster of differentiation 43) is a transmembrane cell surface protein that in humans is encoded by the ''SPN'' (sialophorin) gene.
Function
Sialophorin (leukosialin) is a major sialoglycoprotein ...
and
CD45
Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the ''PTPRC'' gene. PTPRC is also known as CD45 antigen (CD stands for cluster of differentiation), which was originally called leuko ...
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
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
and a
dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...
.
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
The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...
based mainly on similar
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
rearrangement, orientation of the
centrosome
In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle prog ...
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 Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates ...
present in the p-SMAC of a
T-cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
, and non-specific adhesion molecules (such as
ICAM-1
ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial ...
or
ICAM-2
Intercellular adhesion molecule 2 (ICAM2), also known as CD102 (Cluster of Differentiation 102), is a human gene, and the protein resulting from it.
Protein structure
The protein encoded by this gene is a member of the intercellular adhesion mol ...
) 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
In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle prog ...
toward the site of the immunological synapse. The symmetric centripetal actin flow is 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
Arp2/3 complex (Actin Related Protein 2/3 complex) is a seven-subunit protein complex that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the actin cytoskeleton and is found in most actin cytoskeleton- ...
, 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
A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...
, the synapse formation leads to killing of the target cell via secretion of cytolytic enzymes.
CD8+ T lymphocytes contain lytic granules – specialized secretory
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
s filled with
perforin
Perforin-1 is a protein that in humans is encoded by the ''PRF1'' gene and the ''Prf1'' gene in mice.
Function
Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK cel ...
,
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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. 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.
NK-cell synapse
NK cells
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
are known to form synapses with cytolytic effect towards the target cell. In the initiation step, NK cell approaches the target cell, either accidentally or intentionally due to the chemotactic signalling. Firstly, the
sialyl Lewis X
Sialyl LewisX (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide carbohydrate which is usually attached to O- glycans on the surface of cells. It is known to play a vi ...
present on the surface of target cell is recognized by
CD2
CD2 (cluster of differentiation 2) is a cell adhesion molecule found on the surface of T cells and natural killer (NK) cells.
It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette rece ...
on NK cell. If the
KIR receptors of NK cell find their cognate antigen on the surface of target cell, formation of the lytic synapse is inhibited.
If such signal is missing, a tight adhesion via
LFA1 and MAC1 is promoted and enhanced by additional signals such as
CD226
CD226 (Cluster of Differentiation 226), PTA1 (outdated term, 'platelet and T cell activation antigen 1') or DNAM-1 ( DNAX Accessory Molecule-1) is a ''~65 kDa'' immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural k ...
-ligand and
CD96
CD96 (Cluster of Differentiation 96) or Tactile (T cell activation, increased late expression) is a protein that in humans is encoded by the ''CD96'' gene. CD96 is a receptor protein which is expressed on T cells and NK cells and shares sequ ...
-
CD155 interactions.
Lytic granules are secretory organelles filled with
perforin
Perforin-1 is a protein that in humans is encoded by the ''PRF1'' gene and the ''Prf1'' gene in mice.
Function
Perforin is a pore forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK cel ...
,
granzymes and other cytolytic enzymes. After initiation of the cell-cell contact, the lytic granules of NK cells move around the
microtubule
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...
s towards the
centrosome
In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle prog ...
, which also relocalizes towards the site of synapse. Then, the contents of lytic granules is released and via vesicles with
SNARE proteins transferred to the target cell.
Inhibitory immunological synapse of NK cells
When an NK cell encounters a self cell, it forms a so-called inhibitory immunological synapse to prevent unwanted cytolysis of target cell. In this process, the
killer-cell immunoglobulin-like receptors (KIRs) containing long cytoplasmic tails with
immunoreceptor tyrosine-based inhibitory motifs (ITIMs) are clustered in the site of synapse, bind their ligand on the surface of target cell and form the supramolecular inhibitory cluster (SMIC). SMIC then acts to prevent rearrangement of
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
, block the recruitment of activatory receptors to the site of synapse and finally, promote detachment from the target cell. This process is essential in protecting NK cells from killing self cells.
History
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
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and repres ...
, and published this around the same time.
Abraham Kupfer first presented his findings during one of th
Keystone symposiain 1995, when he showed three-dimensional images of immune cells interacting with one another. Key molecules in the synapse are the
T cell receptor
The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...
and its counterpart the
major histocompatibility complex
The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...
(MHC). Also important are
LFA-1 Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates ...
,
ICAM-1
ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial ...
,
CD28
CD28 (Cluster of Differentiation 28) is one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival. T cell stimulation through CD28 in addition to the T-cell receptor ( TCR) can provid ...
, and
CD80
The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...
/
CD86
Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD ...
.
References
External links
Immunological Synapse - Cell Centered Database
{{DEFAULTSORT:Immunological Synapse
Immune system