Immunological synapse

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.[1] It is the subject of much ongoing research.[2]

Structure and Function

The immune synapse is also known as the supramolecular activation cluster or SMAC.[3] This structure is composed of concentric rings (often referred to as a bull’s eye model of the immunological synapse) each containing segregated clusters of proteins:

New investigations, however, have shown that the original bull’s eye model is not present in all immunological synapses. For example, different patterns appear in the synapse between T-cell and dendritic cell.[8][9]

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

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 target cell. When binded to the target cell, T-cell can extend pseudopodia and scan the surface of target cell to find a specific peptide:MHC complex.[11][12]

The process of formation begins when T-cell receptor (TCR) binds to the peptide:MHC complex on the APC. Specific signalization pathways lead to polarization of the T-cell by orientation of its centrosome towards 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 complex (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. By this, the process upregulates itself via the positive feedback loop mechanism [13].

Some parts of this process may differ in CD4+ and CD8+ cells. For example, the 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.[11][13] In CD8+ T cells, the synapse formation leads to killing of the target cell via secretion of cytolytic enzymes [13].

History

It was first discovered by Abraham Kupfer at the National Jewish Medical and Research Center in Denver and the term was coined by Michael Dustin at NYU who studied it 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.[14] 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.

References

  1. ↑ Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (July 1999). "The immunological synapse: a molecular machine controlling T cell activation". Science. 285 (5425): 221–227. PMID 10398592. doi:10.1126/science.285.5425.221.
  2. ↑ "What is the importance of the immunological synapse?" (PDF).
  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. PMID 9738502. doi:10.1038/25764.
  4. ↑ Monks CR, Kupfer H, Tamir I, Barlow A, Kupfer A (January 1997). "Selective modulation of protein kinase C-theta during T-cell activation". Nature. 385 (6611): 83–86. PMID 8985252. doi:10.1038/385083a0.
  5. ↑ Lee KH, Holdorf AD, Dustin ML, Chan AC, Allen PM, Shaw AS (February 2002). "T cell receptor signaling precedes immunological synapse formation". Science. 295 (5559): 1539–1542. PMID 11859198. doi:10.1126/science.1067710.
  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. PMID 11728332. doi:10.1016/S1074-7613(01)00231-X.
  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. PMID 12244310. doi:10.1038/ni836.
  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. ISSN 0022-1767. PMC 2556893 Freely accessible. PMID 18802089. doi:10.4049/jimmunol.181.7.4852.
  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. ISSN 1521-4141. doi:10.1002/eji.200425857.
  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. PMID 15145322. doi:10.1016/j.it.2004.03.007.
  11. 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. ISSN 1600-065X. PMC 3645447 Freely accessible. PMID 23278741. doi:10.1111/imr.12017.
  12. ↑ Murphy, Kenneth M. (2011-07-25). Janeway's Immunobiology. Taylor & Francis Group. ISBN 9781136665219.
  13. 1 2 3 Ortega-Carrion, Alvaro; Vicente-Manzanares, Miguel (2016-03-31). "Concerning immune synapses: a spatiotemporal timeline". F1000Research. 5. ISSN 2046-1402. PMC 4821290 Freely accessible. PMID 27092248. doi:10.12688/f1000research.7796.1.
  14. ↑ Davis DM, Chiu I, Fassett M, Cohen GB, Mandelboim O, Strominger JL (Dec 1999). "The human natural killer cell immune synapse". Proc Natl Acad Sci U S A. 96 (26): 15062–7. PMC 24773 Freely accessible. PMID 10611338. doi:10.1073/pnas.96.26.15062.
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