Putting the natural killer cell in its place

Abstract

Natural killer (NK) cells were originally described as 'null' lymphocytes, but we have increasing evidence of their role in recognizing pathogen, and our knowledge of NK cell receptors continues to expand exponentially. Human NK cells have many receptors for human leucocyte antigen (HLA) class I. These killer immunoglobulin-like receptors (KIRs) and CD94/NKG2 receptors can signal in both positive and negative ways to regulate NK cell functions. The inhibitory receptors are the best characterized, but even in these cases much of their functional biology remains elusive. In this review, some recent advances in terms of the three-immunoglobulin (3Ig)-domain KIRs are discussed. Natural cytotoxicity receptors (NCRs) are among the activatory receptors found on NK cells. While pathogen ligands for these receptors have been described, endogenous ligands remain elusive. NCRs and NKG2D, a receptor for stress-induced antigens, appear to play complementary functional roles in terms of NK cell activation. More recently described on NK cells are the Toll-like receptors. In particular, these receptors of the innate immune system allow NK cells to directly sense pathogen, and their ligation on accessory cells indirectly activates NK cells through cytokine production. It is becoming clear that none of these receptor systems functions in isolation and that it is the sum of the signals (which will reflect the pathogenic situation), in addition to the cytokine milieu, that will direct NK cell activation. The resulting cytotoxicity, cytokine production and direct cell-cell regulatory interactions with other cells of the immune system, for example dendritic cells, ultimately determine the role of the NK cell in the context of an overall immune response.

Figure 1

Toll-like receptor 4 (TLR4) is expressed on the surface of human natural killer (NK) cells. All CD56^dim NK cells expressed TLR4 on their cell surface, in contrast to the CD56^bright subset of NK cells. Cells were stained with anti-CD56 (BD Biosciences, Oxford, UK) and anti-TLR4 antibodies (E-biosciences, San Diego, CA), and analysed using a FACSCalibur flow cytometer (Becton Dickenson, Mountain View, CA).

Figure 2

Direct and indirect activation of human natural killer (NK) cells. NK cells receive activation signals via a variety of direct and indirect mechanisms. A number of events occur in a virally infected cell which affect NK cells. Viral protein is processed by the antigen-processing pathway and viral peptide is presented on the surface of the infected cell in the context of human leucoyte antigen (HLA) class I. The altered peptide presented may result in perturbation of an inhibitory signal through a killer immunoglobulin-like receptor (KIR) to the NK cell, resulting in its activation. KIRs are also sensitive to the loss of HLA class I from the cell surface, a mechanism used by some viruses to escape cytotoxic T lymphocyte (CTL) recognition. Type 1 interferon (IFN) is produced by virally infected cells, and this is a potent cytokine in terms of activating NK cell effector functions such as cytotoxicity. Viral antigen, for example haemagglutinin (HA), expressed at the infected cell surface can directly engage NK cell activatory receptors such as NKp46. Direct recognition of viral pathogen can also occur through sensing of viral replication products, for example double-stranded (ds) RNA, through cell surface Toll-like receptor 3 (TLR3). Viral replication products such as single-stranded (ss) and dsRNA can also indirectly activate NK cells by interaction with appropriate TLRs on accessory cells, with resultant production of NK cell stimulatory cytokines such as interleukin (IL)-12. Some similar mechanisms exist in tumour cell recognition, including down-regulation of HLA class I to escape from CTLs which can then result in NK cell activation. Different mechanisms involved include induction of stress antigens, for example MICA and MICB, which activate NK cell effector functions through NKG2D. NK cells thus receive a number of signals dependent on the immunological challenge, which can be both direct and indirect (see above), and it is the balance of these that culminates in the final NK cell response.