Natural Killer cell

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Introduction

Natural killer (NK) cells are a form of cytotoxic lymphocyte which constitute a major component of the innate immune system. NK cells play a major role in the host-rejection of both tumours and virally infected cells. They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells which are "missing self" ("missing-self" recognition is a term used to describe cells with low levels of MHC (major histocompatibility complex) class I cell surface marker molecules—a situation which could arise due to viral infection, or in tumors under strong selection pressure of killer T cells).

NK cells were discovered due to their non-MHC-restricted killer activity that disturbed early attempts to generate tumour-specific, MHC-restricted cytotoxic T lymphocytes (CTLs) from mice shortly after the discovery of the phenomenon of MHC restriction.

They are large granular lymphocytes that do not express T-cell antigen receptors (TCR) or Pan T marker CD3 or surface immunoglobulins (Ig) B cell receptor but which usually express the surface markers CD16 (FcγRIII) and CD56 in humans, and NK1.1/NK1.2 in certain strains of mice.

With the discovery of activating receptors almost two decades after the discovery of the inhibitory receptors these cells continue to be called by the same name, though “natural” does not mean the same any more. However the term “natural killer” continues to be justified by:

  • a morphology characteristic of activated cytotoxic lymphocytes—e.g., large size, high protein synthesis activity in the abundant endoplasmic reticulum (ER, and preformed granules;
  • the mature state (does not require much new protein synthesis and remodelling before starting to kill); and
  • the rapid killing activity observed in freshly isolated NK cells.

NK cells are cytotoxic; small granules in their cytoplasm contain special proteins such as perforin and proteases known as granzymes. Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell through which the granzymes and associated molecules can enter, inducing apoptosis. The distinction between apoptosis and cell lysis is important in immunology— lysing a virus-infected cell would only release the virions, whereas apoptosis leads to destruction of the virus inside.

NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to control viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells that can clear the infection. Patients deficient in NK cells prove to be highly susceptible to early phases of herpes virus infection.

In order for NK cells to defend the body against viruses and other pathogens, they require mechanisms which enable the determination of whether a cell is infected or not. The exact mechanisms remain the subject of current investigation, but recognition of an "altered self" state is thought to be involved. To control their cytotoxic activity, NK cells possess two types of surface receptors: "activating receptors" and "inhibitory receptors". Most of these receptors are not unique to NK cells and can be present in T cell subsets as well.

These inhibitory receptors recognize MHC class I alleles, which could explain why NK cells kill cells possessing low levels of MHC class I molecules.

NK cell receptor types (with inhibitory as well as some activating members) are differentiated by structure:

  1. CD94 : NKG2 (heterodimers) — a C-type lectin family receptor, conserved in both rodents and primates and identifies non-classical (also non-polymorphic) MHC I molecules like HLA E. Though indirect, this is a way to survey the levels of classical (polymorphic) HLA molecules, however, because expression of HLA-E at the cell surface is dependent upon the presence of classical MHC class I leader peptides.
  2. Ly49 (homodimers) — a relatively ancient, C-type lectin family receptor; are of multigenic presence in mice, while humans have only one pseudogenic Ly49; the receptor for classical (polymorphic) MHC I molecules.
  3. KIR (Killer cell Immunoglobulin-like Receptors) — belong to a multigene family of more recently-evolved Ig-like extracellular domain receptors; are present in non- rodent primates; and are the main receptors for both classical MHC I (HLA A,HLA B,HLA C) and also non-classical HLA G in primates. Some KIRs are specific for certain HLA subtypes.
  4. ILT or LIR (leucocyte inhibitory receptors) — are recently-discovered members of the Ig receptor family.


Literature

  • Immunobiology The Immune System In Health And Disease by Janeway, Travers, Walport & Shlomchik Churchchill Livingstone Copyright 2005
  • Cellular and Molecular Immunology by Abbul K. Abbas & Andrew Lichtman Saunders Copyright 2003
  • How the Immune System Works, 2nd edition, by Lauren Sompayrac, PhD Blackwell Publishing 2003

Natural killer cells: from "disturbing" background to central players of immune responses

Hokland and Kuppen (Mol Immunol., 2005) focus on history and present of NK cell science in their editorial, introducing into a special issue of the journal "Molecular Immunology" presenting some highlights from the 8th Meeting of the Society for Natural Immunity (May 2004, Nordwijkerhout, NL). They describe initial "accidential" discovery of NK cells in the early 1970s (Baldwin 1973, Bubenik 1971, Hellstrom 1974, Leventhal 1972, O'Toole 1974, Takasugi 1973) when assessing specific cytotoxic effects of lymphocytes against tumor cell lines. Cytotoxicity without prior immunization against cells infected with viruses again were in contradiction to paradigms of T cell mediated immunology (Labowskie 1974, Rola-Pleszczynski 1975, Steele 1973). "Spontaneous" cytotoxicity then was termed natural killing by Kiessling (1975a, 1975b) and Herbermann (1975a, 1975b).

NK cell development

The human spleen is involved in the generation of NK cells from circulating progenitors: Human spleen-derived fibroblasts display a differentiated myofibroblast phenotype and constitutively express a biologically active form of membrane bound IL-15. IL-15 can drive co-cultured CD34+ progenitors to differentiate into activated NK cells. (Briard D et al., 2005).

Di Santo (Annu Rev Immunol. 2006, PMID:16552715) describes that balancing signals to NK cell precursors is crucial for their early development and that several major issues remain to be addressed, such as identifying the sites for NK cell maturation and defining the peripheral NK cell niche.

NK cell receptors

Different families of NK cell receptors exist and many of these receptors seem to have evolved recently. NK cell receptors can both have activating or inhibitory function.

As part of the receptor repertoire of NK cells have been observed:

Gays et al. (2005, [1]) demonstrated that in contrast to earlier assumptions the NK cell receptor repertoire is not fixed but can be remodeled by cytokines. They showed that IL-2 and IL-15 selectively induced the de novo expression of Ly49E on murine mature NK cells. IL-4 essentially eliminated expression of pre-existing CD94/NKG2 receptors on NK cells. IL-21 virtually ablated expression of Ly49F and reduced the level of expression of NKRP1C.

NK cells and diseases

NK-inhibitory receptor CEACAM1 (carcino-embryonic antigen-cell adhesion molecule) is highly expressed among NK cells derived from Ankylosing Spondylitis patients but not from healthy controls. NK cells and CEACAM1 play a role in AS pathogenesis and implicate chemokines (IL-8, SDF-1)in the mechanism of CEACAM1 expression (Azuz-Lieberman, 2005 [2]).

Richards et al. (Blood 2006, PMID:16556890) demonstrated that multiple lineages of tumors, including thymoma, breast cancer, colon cancer and melanoma cell lines interrupt functional maturation during NK cell development in the murine bone marrow. The defect in IFN-gamma production but not cytotoxicity was associated with a significant reduction in the IL-15Ralpha(-)positive cells in the non-T, non-NK compartment of bone marrow cells. They demonstrate that tumor growth can impede functional maturation of NK cells, most likely by interrupting the requisite IL-15 signaling pathway.

See also

Literature and References

latest highlights

Nature Immunology - Focus on NK cells (2008)

Selected Literature 2003 - 2005

Immunobiology of Natural Killer Cell Receptors
Eric Vivier, Marco Colonna ISBN 3540260838

Immunobiology The Immune System In Health And Disease by Janeway, Travers, Walport & Shlomchik Churchchill Livingstone Copyright 2005 (see NCBI Bookshelf)

Cellular and Molekular Immunology by Abbul K. Abbas & Andrew Lichtman Saunders Copyright 2003

Hokland M, Kuppen PJ.
Natural killer cells: from "disturbing" background to central players of immune responses.
Mol Immunol. 2005 Feb;42(4):381-3.

Perussia B, Loza MJ.
Purification of peripheral blood natural killer cells.
Methods Mol Med. 2004;107:147-62. PMID: 15492370

Multiple Cytokines Regulate the NK Gene Complex-Encoded Receptor Repertoire of Mature NK Cells and T Cells
Gays, F., Martin, K., Kenefeck, R., Aust, J. G., Brooks, C. G.
J Immunol 2005 175: p. 2938-2947 NKref0481

References for the "Crash Course" (Hokland, Kuppen, 2005) in the natural history of Natural killer cells

Baldwin RW, Embleton MJ, Jones JS, Langman MJ.
Cell-mediated and humoral immune reactions to human tumours.
Int J Cancer. 1973 Jul 15;12(1):73-83. No abstract available. PMID: 4790710

Bubenik J, Jakoubkova J, Krakora P, Baresova M, Helbich P, Viklicky V, Malaskova V.
Cellular immunity to renal carcinomas in man.
Int J Cancer. 1971 Nov 15;8(3):503-13. No abstract available. PMID: 5137312

Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA.
Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes.
J Exp Med. 1982 Jun 1;155(6):1823-41. PMID: 6176669 Free Fulltext

Grossi CE, Cadoni A, Zicca A, Leprini A, Ferrarini M.
Large granular lymphocytes in human peripheral blood: ultrastructural and cytochemical characterization of the granules.
Blood. 1982 Feb;59(2):277-83. PMID: 7055640

Hellstrom I, Hellstrom KE.
Cell-mediated immune reactions to tumor antigens with particular emphasis on immunity to human neoplasms.
Cancer. 1974 Oct;34(4 Suppl):suppl:1461-8. No abstract available. PMID: 4417442

Herberman RB, Nunn ME, Holden HT, Lavrin DH.
Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells.
Int J Cancer. 1975 Aug 15;16(2):230-9. PMID: 1080480

Herberman RB, Nunn ME, Lavrin DH.
Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity.
Int J Cancer. 1975 Aug 15;16(2):216-29. PMID: 50294

Kiessling R, Klein E, Wigzell H.
"Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype.
Eur J Immunol. 1975 Feb;5(2):112-7. PMID: 1234049

Kiessling R, Klein E, Pross H, Wigzell H.
"Natural" killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell.
Eur J Immunol. 1975 Feb;5(2):117-21. PMID: 1086218

Kiessling R, Wigzell H.
An analysis of the murine NK cell as to structure, function and biological relevance.
Immunol Rev. 1979;44:165-208. Review. No abstract available. PMID: 367949

Labowskie R, Edelman R, Rustigian R, Bellanti JA.
Studies of cell-mediated immunity to measles virus by in vitro lymphocyte-mediated cytotoxicity.
J Infect Dis. 1974 Mar;129(3):233-9. No abstract available. PMID: 4816303

Leventhal BG, Halterman RH, Rosenberg EB, Herberman RB.
Immune reactivity of leukemia patients to autologous blast cells.
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=4264526 Cancer Res. 1972 Sep;32(9):1820-5. No abstract available. PMID: 4264526

O'Toole C, Stejskal V, Perlmann P, Karlsson M.
Lymphoid cells mediating tumor-specific cytotoxicity to carcinoma of the urinary bladder. Separation of the effector population using a surface marker.
J Exp Med. 1974 Mar 1;139(3):457-66. No abstract available. PMID: 4591169

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Initial version of this article from Wikipedia, the free encyclopedia. Further edited as an collaborative approach to focus on information related to Natural Killer cells and Innate Immunity.

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