Natural Killer Cell: Difference between revisions

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The prominent inhibitory ligand of NK cells that were originally used to distinguish between them and the killer T cells was MHC class I molecules<ref>1,2</ref> When first discovered, NK cells’ cytotoxicity was said to be non-restricted by MHC.<ref>1,2</ref> However, it was later discovered that NK cells specifically lyse infected, tumorous or MHC-deficient cells that lack MHC class I on their surfaces <ref>5</ref>, which make them undetectable by killer T cells. This gave rise to the “missing self” hypothesis in the 1990s.<ref>Ljunggren, H.-G., & Kärre, K. (1990). In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunology Today, 11, 237–244. doi: 10.1016/0167-5699(90)90097-s</ref> The hypothesis was later expanded to the “zipper” model of NK cell activation. which includes a range of identified inhibitory and activating receptors and their corresponding ligands on NK cells’ membrane.<ref>Vivier, E., Tomasello, E., Baratin, M., Walzer, T., & Ugolini, S. (2008). Functions of natural killer cells. Nature Immunology, 9(5), 503–510. Retrieved from: https://doi-org.libproxy.kenyon.edu/10.1038/ni1582</ref>
The prominent inhibitory ligand of NK cells that were originally used to distinguish between them and the killer T cells was MHC class I molecules<ref>1,2</ref> When first discovered, NK cells’ cytotoxicity was said to be non-restricted by MHC.<ref>1,2</ref> However, it was later discovered that NK cells specifically lyse infected, tumorous or MHC-deficient cells that lack MHC class I on their surfaces <ref>5</ref>, which make them undetectable by killer T cells. This gave rise to the “missing self” hypothesis in the 1990s.<ref>Ljunggren, H.-G., & Kärre, K. (1990). In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunology Today, 11, 237–244. doi: 10.1016/0167-5699(90)90097-s</ref> The hypothesis was later expanded to the “zipper” model of NK cell activation. which includes a range of identified inhibitory and activating receptors and their corresponding ligands on NK cells’ membrane.<ref>Vivier, E., Tomasello, E., Baratin, M., Walzer, T., & Ugolini, S. (2008). Functions of natural killer cells. Nature Immunology, 9(5), 503–510. Retrieved from: https://doi-org.libproxy.kenyon.edu/10.1038/ni1582</ref>
<br><b>NK cells’ coevolution with viral pathogens</b><br>
<br><b>NK cells’ coevolution with viral pathogens</b><br>
A hypothesis has been proposed that NK cells evolved to fill the immunological niche created by the evolution of certain pathogens and tumor cell types to downregulate MHC class I in their host cells (the main way for infected cells to present antigens and signal their “infected” state to killer T cells) and evade cytolysis by killer T cells. Example cases can be seen in murine cytomegalovirus, human cytomegalovirus, HIV and herpes simplex virus.<ref>Lodoen, M. B., & Lanier, L. L. (2005). Viral modulation of NK cell immunity. Nature Reviews Microbiology, 3(1), 59–69. doi: 10.1038/nrmicro1066</ref>
A hypothesis has been proposed that NK cells evolved to fill the immunological niche created by the evolution of certain pathogens and tumor cell types to downregulate MHC class I in their host cells (the main way for infected cells to present antigens and signal their “infected” state to killer T cells) and evade cytolysis by killer T cells. Example cases can be seen in murine cytomegalovirus, human cytomegalovirus, HIV and herpes simplex virus.<ref>Lodoen, M. B., & Lanier, L. L. (2005). Viral modulation of NK cell immunity. Nature Reviews Microbiology, 3(1), 59–69. doi: 10.1038/nrmicro1066</ref>



Revision as of 05:12, 2 December 2019

Overview

Natural killer cells (NK cells) under light microscopy (A) and electron microscopy (B). In Characterization of a Novel Human Natural Killer-Cell Line (NK-YS) Established From Natural Killer Cell Lymphoma/Leukemia Associated With Epstein-Barr Virus Infection (Tsuchiyama J. et al. 1998). Link:https://ashpublications.org/blood/article/92/4/1374/247309/Characterization-of-a-Novel-Human-Natural-Killer

Natural killer cells (NK cells) are a type of granular cytotoxic lymphocytes that are non-adherent and non-phagocytic. NK cells were originally defined as a subset of lymphocytes that have natural cytotoxic activity against certain types of tumorous cells and endogenous type-C viruses in mice. Natural cytotoxicity refers to the fact that they can rapidly cause tumor cells’ lyses in the absence of any previous stimulation [1],[2]. They were first named in an article in 1976 [3] and later categorized as part of the innate immune system due to their morphology, origin (bone marrow), and lack of antigen-specific receptors (such as those on T and B-cells’ surfaces) and their respective genes.[4],[5]









Cytotoxic function of NK cells. In Innate or Adaptive Immunity? The Example of Natural Killer Cells (Vivier et al. 2011). Link:https://science.sciencemag.org/content/331/6013/44/F3
Regulation of immune responses by NK cells. In Functions of Natural Killer cells (Vivier et al. 2008). Link: https://www.semanticscholar.org/paper/Functions-of-natural-killer-cells-Vivier-Tomasello/25da9b199edde64037499489383fe4f4199460f3

NK cells share many features with leukocytes of the innate immune system, such as: granular cytoplasm, spontaneous activity, and susceptibility to positive regulation by immune stimuli (dendritic cells’ cytokinin).[6] However, research has shown that NK cells can retain antigen-specific immunological memory [7], characteristics common to T and B-cells of the adaptive immune system, and interact with T-cells and macrophages to control immune response [8],[9], a role which is usually associated with regulatory T-cells. Furthermore, studies into the immunological reactions against cytomegalovirus in mice and human has generated evidences that certain subsets of NK cells can be activated and stimulated to multiply in response to specific pathogens.[10],[11] Thus, NK cells are now considered to be a conjunction point of both the innate and adaptive immune systems.

NK cells share a similar cytolytic mechanism of granule-exocytosis[12] with killer T cells where they utilize the two crucial cytolytic enzyme: perforin and granzyme.[13],[14],[15] Moreover, NK cells also induce apoptosis in target cells by the Fas-mediated pathway using the Fas ligands.[16] However, unlike T and B cells of the adaptive immune system, NK cells do not rely on antigen presentation by the major histocompatibility complex (MHC) class I on cells’ membranes to be activated, rather, they utilize a combination of membranal markers to distinguish between the “self” and “non-self” (or “infected self”).[17] This enables NK cells to recognize tumor and infected, especially virally infected, cells without previous stimulation, which resulted in rapid and “natural” cytotoxicity. Apart from the first discovered and well-known immunosurveillance against tumor cells[18],[19], NK cells also play important roles in containing a number of microbial and viral infections (such as: cytomegalovirus, HIV-1, herpesvirus and the malaria parasite)[20],[21] as well as in early stages of pregnancy.[22]



Subscript: H2O
Superscript: Fe3+



Mechanism of NK cells’ cytotoxicity

Natural killer cell with perforin-containing granules. (credit: modification of work by Rolstad B). Link: https://courses.lumenlearning.com/microbiology/chapter/cellular-defenses/

One of NK cells’ originally-described morphological characteristics was the granules inside their cytoplasm, similar to what seen in macrophages.[23] However, later research revealed that these granules bear more similarity to those in stimulated killer T-cells than those in macrophages, and are the effector organelles of cytolysis caused by killer T-cells and NK cells.[24] Granules in NK cells (and also stimulated killer T cells) contain proteins responsible for signaling and facilitating cell apoptosis, the most well understood of which are perforin, granzyme, calreticulin, and glycosaminoglycan.[25] The cytolytic granules also contain Fas ligands, which facilitate the Fas-medicated cytotoxicity of NK cells coexisting with the granule-exocytosis pathway[26], and granulysin but knowledge about its biochemical pathways and significance within the cytolytic granules are limited.[27]


Granule-exocytosis and Fas-mediated pathways of NK cell-mediated cytotoxicity. http://flipper.diff.org/app/items/info/4636

The Granule-exocytosis model

After NK cells form bindings of their membranal receptors with ligands on the surfaces of their neighboring cells, if the binding cells are recognized as alien, “stressed” or “infected” (target cells), cytolytic granules in NK cells are transported to the site of cell contacts and fuse with NK cells’ membrane to release the cytolytic enzymes into the space between the cells’ synapses. There, perforin creates pores to form transport channels on the target cells’ membrane and other accessory proteins chaperon granzyme into the target cells, where it signals different processes of cytolysis.[28] Exact functions of different types of granzyme, apart from the prominent, heavily studied granzyme B, are yet to be understood.


Fas-mediated apoptosis of target cells

To be updated.





“Self – non-self” recognition by NK cells/ The “missing self” hypothesis

“Zipper” module of NK cells activation. In Functions of Natural Killer cells (Vivier et al. 2008). Link: https://www.semanticscholar.org/paper/Functions-of-natural-killer-cells-Vivier-Tomasello/25da9b199edde64037499489383fe4f4199460f3

NK cells have a set of inhibitory and activating receptors on their cells’ surface that binds to specific syngeneic membranal molecules (ligands) on other cells’ membranes. A “normal” combination of these binding signals (which was established by a process of NK cell education for self-tolerance [29]) would result in NK cells remaining dormant. However, if NK cells bind to other cells that present an abnormal combination of activating and inhibitory ligands on their membranes, they are activated and release cytolytic signals into the binding cells. This mechanism allows NK cells to specifically surveil for “stressed” or “altered state” cells.[30],[31]

The prominent inhibitory ligand of NK cells that were originally used to distinguish between them and the killer T cells was MHC class I molecules[32] When first discovered, NK cells’ cytotoxicity was said to be non-restricted by MHC.[33] However, it was later discovered that NK cells specifically lyse infected, tumorous or MHC-deficient cells that lack MHC class I on their surfaces [34], which make them undetectable by killer T cells. This gave rise to the “missing self” hypothesis in the 1990s.[35] The hypothesis was later expanded to the “zipper” model of NK cell activation. which includes a range of identified inhibitory and activating receptors and their corresponding ligands on NK cells’ membrane.[36]


NK cells’ coevolution with viral pathogens
A hypothesis has been proposed that NK cells evolved to fill the immunological niche created by the evolution of certain pathogens and tumor cell types to downregulate MHC class I in their host cells (the main way for infected cells to present antigens and signal their “infected” state to killer T cells) and evade cytolysis by killer T cells. Example cases can be seen in murine cytomegalovirus, human cytomegalovirus, HIV and herpes simplex virus.[37]

Conclusion

Overall text length should be at least 1,000 words (before counting references), with at least 2 images. Include at least 5 references under Reference section.


References

  1. Herberman, R. B., Nunn, M. E., Holden, H. T. and Lavrin, D. H. (1975), Natural cytotoxic rectivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int. J. Cancer, 16: 230-239. doi:10.1002/ijc.2910160205
  2. Herberman, R. B., Nunn, M. E. and Lavrin, D. H. (1975), Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. I. Distribution of reactivity and specificity. Int. J. Cancer, 16: 216-229. doi:10.1002/ijc.2910160204
  3. WOLFE, S., TRACEY, D. & HENNEY, C. Induction of “natural killer” cells by BCG. Nature 262, 584–586 (1976) doi:10.1038/262584a0
  4. Eidenschenk, C., Dunne, J., Jouanguy, E., Fourlinnie, C., Gineau, L., Bacq, D., … Feighery, C. (2006). A Novel Primary Immunodeficiency with Specific Natural-Killer Cell Deficiency Maps to the Centromeric Region of Chromosome 8. The American Journal of Human Genetics, 78(4), 721–727. doi: 10.1086/503269
  5. Trinchieri, G. Biology of natural keller cells. Adv. Immunology. Volume 47, 187-376 (1989). doi: 10.1016/S0065-2776(08)60664-1
  6. Trinchieri, G. Biology of natural keller cells. Adv. Immunology. Volume 47, 187-376 (1989). doi: 10.1016/S0065-2776(08)60664-1
  7. Sun, J., Beilke, J. & Lanier, L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009) doi:10.1038/nature07665
  8. Raulet, D. Interplay of natural killer cells and their receptors with the adaptive immune response. Nat Immunol 5, 996–1002 (2004) doi:10.1038/ni1114
  9. Dommelen, S. L. V., Sumaria, N., Schreiber, R. D., Scalzo, A. A., Smyth, M. J., & Degli-Esposti, M. A. (2006). Perforin and Granzymes Have Distinct Roles in Defensive Immunity and Immunopathology. Immunity, 25(5), 835–848. doi: 10.1016/j.immuni.2006.09.010
  10. Dokun, A. O., Kim, S., Smith, H. R., Kang, H.-S. P., Chu, D. T., & Yokoyama, W. M. (2001). Specific and nonspecific NK cell activation during virus infection. Nature Immunology, 2(10), 951–956. doi: 10.1038/ni714
  11. Walter, L. (2011). Faculty of 1000 evaluation for Expansion of a unique CD57⁺NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. F1000 - Post-Publication Peer Review of the Biomedical Literature. doi: 10.3410/f.12631956.13874054
  12. Henkart M.P., Henkart P.A. (1982) Lymphocyte Mediated Cytolysis as a Secretory Phenomenon. In: Clark W.R., Golstein P. (eds) Mechanisms of Cell-Mediated Cytotoxicity. Advances in Experimental Medicine and Biology, vol 146. Springer, Boston, MA
  13. Dommelen, S. L. V., Sumaria, N., Schreiber, R. D., Scalzo, A. A., Smyth, M. J., & Degli-Esposti, M. A. (2006). Perforin and Granzymes Have Distinct Roles in Defensive Immunity and Immunopathology. Immunity, 25(5), 835–848. doi: 10.1016/j.immuni.2006.09.010
  14. Lowin, B., Beermann, F., Schmidt, A., & Tschopp, J. (1994). A null mutation in the perforin gene impairs cytolytic T lymphocyte- and natural killer cell-mediated cytotoxicity. Proceedings of the National Academy of Sciences, 91(24), 11571–11575. doi: 10.1073/pnas.91.24.11571
  15. Mahrus, S., & Craik, C. S. (2005). Selective Chemical Functional Probes of Granzymes A and B Reveal Granzyme B Is a Major Effector of Natural Killer Cell-Mediated Lysis of Target Cells. Chemistry & Biology, 12(5), 567–577. doi: 10.1016/j.chembiol.2005.03.006
  16. Oshimi, Y., Oda, S., Honda, Y., Nagata, S., & Miyazaki, S. (n.d.). Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells. The Journal of Immunology, 157(7), 2909–2915
  17. Vivier, E., Tomasello, E., Baratin, M., Walzer, T., & Ugolini, S. (2008). Functions of natural killer cells. Nature Immunology, 9(5), 503–510. Retrieved from: https://doi-org.libproxy.kenyon.edu/10.1038/ni1582
  18. 1-3
  19. 5
  20. Cerwenka, A., & Lanier, L. L. (2001). Natural Killer Cells, Viruses and Cancer. Nature Reviews Immunology, 1(1), 41. Retrieved from link: https://doi-org.libproxy.kenyon.edu/10.1038/35095564
  21. Lodoen, M. B., & Lanier, L. L. (2006, August). Natural killer cells as an initial defense against pathogens. Current Opinion in Immunology, 18(4), 391–398. doi: https://doi.org/10.1016/j.coi.2006.05.002
  22. Vivier, E., Tomasello, E., Baratin, M., Walzer, T., & Ugolini, S. (2008). Functions of natural killer cells. Nature Immunology, 9(5), 503–510. Retrieved from: https://doi-org.libproxy.kenyon.edu/10.1038/ni1582
  23. 1,2
  24. Henkart M.P., Henkart P.A. (1982) Lymphocyte Mediated Cytolysis as a Secretory Phenomenon. In: Clark W.R., Golstein P. (eds) Mechanisms of Cell-Mediated Cytotoxicity. Advances in Experimental Medicine and Biology, vol 146. Springer, Boston, MA
  25. Russell, J. H., & Ley, T. J. (2002). Lymphocyte-Mediated Cytotoxicity. Annual Review of Immunology, 20(1), 323–370. doi: 10.1146/annurev.immunol.20.100201.131730
  26. Oshimi, Y., Oda, S., Honda, Y., Nagata, S., & Miyazaki, S. (n.d.). Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells. The Journal of Immunology, 157(7), 2909–2915
  27. Russell, J. H., & Ley, T. J. (2002). Lymphocyte-Mediated Cytotoxicity. Annual Review of Immunology, 20(1), 323–370. doi: 10.1146/annurev.immunol.20.100201.131730
  28. Russell, J. H., & Ley, T. J. (2002). Lymphocyte-Mediated Cytotoxicity. Annual Review of Immunology, 20(1), 323–370. doi: 10.1146/annurev.immunol.20.100201.131730
  29. Anfossi, N., André, P., Guia, S., Falk, C. S., Roetynck, S., Stewart, C. A., … Vivier, E. (2006). Human NK Cell Education by Inhibitory Receptors for MHC Class I. Immunity, 25(2), 331–342. doi: 10.1016/j.immuni.2006.06.013
  30. Lou, Z., Jevremovic, D., Billadeau, D. D., & Leibson, P. J. (2000). A Balance between Positive and Negative Signals in Cytotoxic Lymphocytes Regulates the Polarization of Lipid Rafts during the Development of Cell-Mediated Killing. Journal of Experimental Medicine, 191(2), 347–354. doi: 10.1084/jem.191.2.347
  31. Davis, D. M., Chiu, I., Fassett, M., Cohen, G. B., Mandelboim, O., & Strominger, J. L. (1999). The human natural killer cell immune synapse. Proceedings of the National Academy of Sciences, 96(26), 15062–15067. doi: 10.1073/pnas.96.26.15062
  32. 1,2
  33. 1,2
  34. 5
  35. Ljunggren, H.-G., & Kärre, K. (1990). In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunology Today, 11, 237–244. doi: 10.1016/0167-5699(90)90097-s
  36. Vivier, E., Tomasello, E., Baratin, M., Walzer, T., & Ugolini, S. (2008). Functions of natural killer cells. Nature Immunology, 9(5), 503–510. Retrieved from: https://doi-org.libproxy.kenyon.edu/10.1038/ni1582
  37. Lodoen, M. B., & Lanier, L. L. (2005). Viral modulation of NK cell immunity. Nature Reviews Microbiology, 3(1), 59–69. doi: 10.1038/nrmicro1066


Edited by [Minh Pham], student of Joan Slonczewski for BIOL 116 Information in Living Systems, 2019, Kenyon College.