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Role(s) of NK cells:
Natural killer cells mediate the immediate killing of tumor cells, virally infected cells and tissue graft
cells. Eliminating NK cells in vivo increases the rate of growth of tumours and the severity of viral diseases.
Rapidly proliferating cells like bone marrow cells and tumor cells are most easily killed and slowly growing
differentiated cells are poor targets. As such NK-cells cause cellular resistance in irradiated hybrid recipients
to grafts of parental bone marrow (B6D2F1 rejects C57Bl/6 and DBA/2 marrow). Therefore, NK cells may
also have a role to play in the negative regulation of endogenous proliferative responses.
More recently, natural killer cells have been shown to be capable of producing a variety of cytokines
including interferon-γ, which may enhance the activation of Th1 responses leading to enhanced T-cell
mediated immunity, which may help the development of immune resistance to viral pathogens. Natural killer
cells can produce a surprising variety of cytokines, including interferons-α and IFN-γ, TNFα, IL-4, IL-1 and
possibly CSF. It is further possible that depending on the relative concentrations of the cytokines expressed,
that the NK cell could indirectly influence the nature of the immune response by inducing Th0
differentiation into either Th1 or Th2.
Mechanism of NK cytotoxicity:
Natural killer cells can directly kill targets to which they are capable of adhering within 1-4 hours
without prior activation, priming or assistance by cytokines. Adherence can be by antibody or complement
component C3b as NK cells have FcγR and C3bR that allow them to produce antibody-dependent cellular
cytotoxicity. Therefore, NK cells are also known as "K" cells when they participate in certain
Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) reactions against opsonized microbes or tumor
cells. NK cells express membrane receptors for IgG (FcγRIII / CD16) and inactivated third component of
complement (iC3b Receptor or CR3 / CD11b). Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
reactions are effective against opsonized microbes, parasites or tumor cells. Further, if the NK cells are
"glued" to targets by lectins like concanavaline A, they are also capable of killing the target cells. The actual
receptors used by NK cells to attach to target cells are lectin-like transmembrane receptors. Most of these
receptors, many of which can mediate antagonistic effects on cytotoxicity, are type II membrane proteins
with a C-type lectin motif, which preferentially bind MHC-I antigens. In the mouse, these receptors are
associated with a complex of genes in the distal arm of mouse chromosome 6 near Prp. Homologues of this
NK gene complex that control NK function exist in the mouse, rat (Chromosome 4) and human
(Chromosome 12). These receptors are conserved and therefore presumably important for overall health.
The gene complex is multigenic (many similar genes with 60-90% homology but different reactivities) and
may have a limited number of alleles for each gene locus, the expression of which is selected in an unknown
manner without allelic exclusion except within a locus. Therefore, NK cells can simultaneously express
several different lectin-type receptors and show specificity for multiple target cell antigens and different
target cells. Similarly, not all NK cells will express all the same NK receptors so the population is also
heterogeneous with respect to specificity for target cells.
Lymphokine activated killers (LAK) (See NK section) are induced by the direct administration of
soluble cytokines: IL-2 and/or IFNα. NK cells activated to become LAK cells with IL-2, used in LAK
therapy successful using PBL or tumor infiltrating lymphocytes (TIL) effectors. Aspirin or indomethacin
inhibits PG synthase inhibits PGE and may be effective therapy when combined with LAK therapy.
Advantages: Well tolerated by patients, effective against a wide variety of primary and secondary cancers.
Disadvantages: Cytokines are expensive; Rapidly cleared from the circulation; Toxic side effects are
common.
2. First line of defence against spontaneously arising tumor cells and against viral infection. Kill cells
with low or absent expression of MHC on cell membranes.
NK cell similarity to T cells:
- Express another T cell marker, CD2
- Express low affinity IL-2R and proliferate in response to high doses of IL-2.
- Express a low-affinity receptor for IgG; FcγRIII = CD16
- Express the transmembrane signalling chain of the CD3 complex; ζ (zeta)
BUT: NK cells have no smIg or TCR-like idiotypic receptor for the recognition of specific antigen; they
may also be triggered to proliferate or to generate cytolytic function in the presence of cytokines
alone (Type I IFNs, IFN-γ, IL-2, TNF-α). Recognition involves either an Ig-like or lectin-like
receptor for target cell monomorphic autologous MHC-I epitopes or carbohydrate (α3 domain)
respectively. These receptors either activate or inhibit killing depending on their cytoplasmic cell-
activation motifs (ITAM/ITIM).
3. Activated by the T-cell derived cytokine Interleukin-2 (IL-2), produced during a specific immune
response, to become Lymphokine Activated Killer (LAK) Cells.
LAK cells are effective in the treatment of malignant melanoma or renal cell carcinoma in
approximately 20-40% of cases tested:
i. Patient peripheral blood LGL + IL-2 ----> LAK cells
ii. LAK cells + additional IL-2 ---> transfused to patient.
iii. In vivo localisation and proliferation of LAK Cells.
iv. Enhanced Tumor Cytotoxicity, mediated by LAK cells.
v. Serious side effect due to IL-2 toxicity (vascular leaking due to TNF and nitric oxide).
PHGY513NKiller-Note.doc