Natural killer cells

NK cells are cytotoxic lymphocytes that lack expression of a T-cell receptor and whose primary function is to kill cells that have downregulated expression of MHC class I molecules. NK cells express a range of inhibitory and activating receptors and it is the balance of signals received through these molecules that determines whether or not the target cell will be killed.

The inhibitory signals include: (i) killer inhibitory receptors (KIRs) that bind to HLA-C or HLA-B alleles on the surface of the target cell and (ii) CD94-NKG2 heterodimers that bind to HLA-E. Activating receptors include: (i) activating forms of KIR molecules, whose ligands are uncertain at present; (ii) NKG2D, which binds to proteins such as MICA and ULBP expressed on cells under physiological stress; and (iii) the immunoglobulin receptor (FcR) CD16.

HLA class I expression is often downregulated on the surface of cells following viral infection and is also a common feature of malignant cells. This provides some protection from recognition by CD8+ T cells but renders the cell susceptible to lysis by NK cells (Figure 20.9). Thus, CD8+ T cells and NK cells can be viewed as having complementary recognition systems based on the level of HLA class I on the target cell. The ability of NK cells to recognize ligands such as MIC-A, which are expressed on the surface of damaged or stressed cells, demonstrates that NK cells may also have the ability to target cells at site of inflammation, irrespective of HLA class I expression level.

Inhibitory KIR

engages HLA class I

Inhibitory KIR

engages HLA class I

Activating receptor binds ligand

No binding ^ of 8

inhibitory

Target cell lysis

Activating receptor binds ligand

class I-deficient , / target cell

Figure 20.9 Mechanism by which NK cells kill target cells that fail to express HLA class I. NK cells express two classes of receptors which either activate (b) or inhibit (a) NK cell killing. The activatory receptors can bind to a range of ligands on the target cell whose expression is often constitutive. In contrast, the major forms of inhibitory receptor bind to HLA class I molecules. If HLA class I expression is downregulated on the target cell, no inhibitory signal is delivered to the NK cells and the target cell is killed.

The lytic mechanisms of NK cells seem to be the same as those used by cytotoxic T cells. NK cells proliferate in the presence of IL-2 and their activity can be augmented by exposure to interferon-y. They characteristically express a range of receptors such as CD56 (NCAM) and CD57 but these are also expressed on a subset of T cells.

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