Immunological synapse

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Immunological synapse between Jurkat T cell expressing GFP-actin (green) and Raji B cell stained with CMAC (blue). Synapse formation was induced by Staphylococcal enterotoxin E superantigen.

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. [1] 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. [2]

Contents

Structure and function

The immune synapse is also known as the supramolecular activation cluster or SMAC. [3] 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:

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. [8] [9]

This complex as a whole is postulated to have several functions including but not limited to:

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. [11] [12]

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. [13] [14]

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-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. [1]

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. [13] [1]

In CD8+ T cells, the synapse formation leads to killing of the target cell via secretion of cytolytic enzymes. [1] 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. [15] 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. [16]

NK-cell synapse

NK cells 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 present on the surface of target cell is recognized by CD2 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. [17] If such signal is missing, a tight adhesion via LFA1 and MAC1 is promoted and enhanced by additional signals such as CD226-ligand and CD96-CD155 interactions. [18]

Lytic granules are secretory organelles filled with perforin, granzymes and other cytolytic enzymes. After initiation of the cell-cell contact, the lytic granules of NK cells move around the microtubules towards the centrosome, 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. [19]

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, 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. [17]

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, and published this around the same time. [20] Abraham Kupfer first presented his findings during a 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.

Related Research Articles

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of 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 receptor (TCR) on their cell surface.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous 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 pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

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. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

<span class="mw-page-title-main">Intraepithelial lymphocyte</span>

Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT).

Ly49 is a family of membrane C-type lectin-like receptors expressed mainly on NK cells but also on other immune cells. Their primary role is to bind MHC-I molecules to distinguish between self healthy cells and infected or altered cells. Ly49 family is coded by Klra gene cluster and include genes for both inhibitory and activating paired receptors, but most of them are inhibitory. Inhibitory Ly49 receptors play a role in the recognition of self cells and thus maintain self-tolerance and prevent autoimmunity by suppressing NK cell activation. On the other hand, activating receptors recognise ligands from cancer or viral infected cells and are used when cells lack or have abnormal expression of MHC-I molecules, which activate cytokine production and cytotoxic activity of NK and immune cells.

NKG2 also known as CD159 is a receptor for natural killer cells. There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to make an inhibitory receptor (CD94/NKG2).

<span class="mw-page-title-main">CD69</span> Human lectin protein

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

<span class="mw-page-title-main">PRKCQ</span> Protein-coding gene in the species Homo sapiens

Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the PRKCQ gene. PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells with high levels in platelets and T lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.

<span class="mw-page-title-main">CD244</span> Protein found in humans

CD244 also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.

<span class="mw-page-title-main">GNLY</span> Protein-coding gene in the species Homo sapiens

Granulysin (GNLY) is a protein expressed in most mammals which functions as an antimicrobial peptide released by killer lymphocytes in cytotoxic granules. It is a pore-forming peptide, as it can puncture a microbial cell wall, allowing for other death-inducing enzymes to enter the microbe and cause microptosis. GNLY is inhibited by cholesterol, and is most effective in helping to kill cholesterol-deficient microbes.

<span class="mw-page-title-main">CD226</span> Protein-coding gene in the species Homo sapiens

CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.

<span class="mw-page-title-main">HAVCR2</span> Protein-coding gene in the species Homo sapiens

Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.

<span class="mw-page-title-main">CD160</span> Protein-coding gene in the species Homo sapiens

CD160 antigen is a protein that in humans is encoded by the CD160 gene.

<span class="mw-page-title-main">Trogocytosis</span>

Trogocytosis is when a cell nibbles another cell. It is a process whereby lymphocytes conjugated to antigen-presenting cells extract surface molecules from these cells and express them on their own surface. The molecular reorganization occurring at the interface between the lymphocyte and the antigen-presenting cell during conjugation is also called "immunological synapse".

Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.

<span class="mw-page-title-main">NKG2D</span> Protein-coding gene in the species Homo sapiens

NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.

References

  1. 1 2 3 4 Ortega-Carrion, Alvaro; Vicente-Manzanares, Miguel (2016-03-31). "Concerning immune synapses: a spatiotemporal timeline". F1000Research. 5: 418. doi: 10.12688/f1000research.7796.1 . ISSN   2046-1402. PMC   4821290 . PMID   27092248.
  2. ↑ "What is the importance of the immunological synapse?" (PDF). Archived from the original (PDF) on 2017-09-23. Retrieved 2015-10-02.
  3. 1 2 Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A (September 1998). "Three-dimensional segregation of supramolecular activation clusters in T cells". Nature. 395 (6697): 82–86. Bibcode:1998Natur.395...82M. doi:10.1038/25764. PMID   9738502. S2CID   4319319.
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  6. ↑ Delon J, Kaibuchi K, Germain RN (November 2001). "Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin". Immunity. 15 (5): 691–701. doi: 10.1016/S1074-7613(01)00231-X . PMID   11728332.
  7. ↑ Freiberg BA, Kupfer H, Maslanik W, Delli J, Kappler J, Zaller DM, Kupfer A (October 2002). "Staging and resetting T cell activation in SMACs". Nat. Immunol. 3 (10): 911–917. doi:10.1038/ni836. PMID   12244310. S2CID   2397939.
  8. ↑ Tseng, Su-Yi; Waite, Janelle C.; Liu, Mengling; Vardhana, Santosha; Dustin, Michael L. (2008-10-01). "T Cell-Dendritic Cell Immunological Synapses Contain TCR-dependent CD28-CD80 Clusters That Recruit Protein Kinase Cθ". The Journal of Immunology. 181 (7): 4852–4863. doi:10.4049/jimmunol.181.7.4852. ISSN   0022-1767. PMC   2556893 . PMID   18802089.
  9. ↑ Brossard, Cédric; Feuillet, Vincent; Schmitt, Alain; Randriamampita, Clotilde; Romao, Maryse; Raposo, Graça; Trautmann, Alain (2005-06-01). "Multifocal structure of the T cell – dendritic cell synapse". European Journal of Immunology. 35 (6): 1741–1753. doi: 10.1002/eji.200425857 . ISSN   1521-4141. PMID   15909310.
  10. 1 2 3 Davis, DM; Dustin, ML (June 2004). "What is the importance of the immunological synapse?". Trends in Immunology. 25 (6): 323–7. CiteSeerX   10.1.1.523.189 . doi:10.1016/j.it.2004.03.007. PMID   15145322. S2CID   16788947.
  11. ↑ Finetti, Francesca; Baldari, Cosima T. (2013-01-01). "Compartmentalization of signaling by vesicular trafficking: a shared building design for the immune synapse and the primary cilium". Immunological Reviews. 251 (1): 97–112. doi:10.1111/imr.12018. ISSN   1600-065X. PMID   23278743. S2CID   28587751.
  12. ↑ Finetti, Francesca; Paccani, Silvia Rossi; Riparbelli, Maria Giovanna; Giacomello, Emiliana; Perinetti, Giuseppe; Pazour, Gregory J.; Rosenbaum, Joel L.; Baldari, Cosima T. (November 2009). "Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse". Nature Cell Biology. 11 (11): 1332–1339. doi:10.1038/ncb1977. ISSN   1476-4679. PMC   2837911 . PMID   19855387.
  13. 1 2 Xie, Jianming; Tato, Cristina M.; Davis, Mark M. (2013-01-01). "How the immune system talks to itself: the varied role of synapses". Immunological Reviews. 251 (1): 65–79. doi:10.1111/imr.12017. ISSN   1600-065X. PMC   3645447 . PMID   23278741.
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  19. ↑ Stow, Jennifer L.; Manderson, Anthony P.; Murray, Rachael Z. (2006). "SNAREing immunity: the role of SNAREs in the immune system". Nature Reviews Immunology. 6 (12): 919–929. doi:10.1038/nri1980. PMID   17124513. S2CID   31267022.
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