NKCell DRAFT

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).

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Discovery

The discovery of NK cells occurred in the early 1970s during research on the well characterized ability of T-lymphocytes to lyse tumour cells against which they had been previously immunized. During these experiments, investigators consistently observed what was termed a natural reactivity, that is: a certain population of cells seemed to be able to lyse tumour cells without having been previously sensitized to them. As these discoveries were incompatible with established model at the time, many of these observations were initially considered artifacts^[1]. However, by 1973 'natural killing' activity was established across a wide variety of species and the existence of a separate lineage of cells possessing this ability was postulated. Through the use of monoclonal antibodies, natural killing ability was mapped to the subset of large, granular lymphocytes known today as NK-cells.

Characteristics

NK-cells are defined as 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 contain 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 other 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.

See also

• Immune system
• Granzymes
• Major histocompatibility complex

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

References

1. ^ Oldham, Robert K. (1983). "Natural Killer Cells: Artifact to Reality". Cancer Metastasis Reviews 2 (4): 323-336.