Natural killer cells and cancer: regulation by the killer cell Ig-like receptors (KIR)

Abstract

Natural killer (NK) cells are innate immune effector cells that make up approximately 10-15% of the peripheral blood lymphocytes in humans and are primarily involved in immunosurveillance to eliminate transformed and virally-infected cells. They were originally defined by their ability to spontaneously eliminate rare cells lacking expression of class I major histocompatibility complex (MHC-I) self molecules, which is commonly referred to as "missing self" recognition. The molecular basis for missing self recognition emerges from the expression of MHC-I-specific inhibitory receptors on the NK cell surface that tolerize NK cells toward normal MHC-I-expressing cells. By lacking inhibitory receptor ligands, tumor cells or virus-infected cells that have down-modulated surface MHC-I expression become susceptible to attack by NK cells. Killer cell Ig-like receptors (KIR; CD158) constitute a family of MHC-I binding receptors that plays a major role in regulating the activation thresholds of NK cells and some T cells in humans. Here, we review the multiple levels of KIR diversity that contribute to the generation of a highly varied NK cell repertoire and explain how this diversity can influence susceptibility to a variety of diseases, including cancer. We further describe strategies by which KIR can be manipulated therapeutically to treat cancer, through the exploitation of KIR/MHC-I ligand mismatch to potentiate hematopoietic stem cell transplantation and the use of KIR blockade to enhance tumor cell killing.

Figure 1. NK cell activity is controlled by the balance of inhibitory and activating receptors

NK cell activity resulting from the interaction of a NK cell with a normal, MHC-I bearing target (A, tolerance) and an abnormal, tumor cell that has lost MHC-I expression (B, activation). Engagement of activating receptors (KIR, NKG2D, CD16 and the NCRs; only NKp44 is shown) with ligands on target cells stimulates NK cell cytotoxicity and the production of cytokines through transmembrane charge-based association with homo- or heterodimers of accessory molecules. The accessory molecules recruit signaling effector molecules (Syk or ZAP-70, phosphatidylinositol 3-kinase (PI3K), or Grb2) to tyrosine phosphorylated (Y-P) cytoplasmic motifs (ITAM or YINM), which mediate downstream activation signaling. Some activating receptor ligands are upregulated after cellular stress, cancerous transformation or viral infection (e.g. the NKG2D ligands, MICA/B and ULBP), further increasing NK cell activity. Normal cells are protected from NK cell-dependent cytotoxicity through the engagement of inhibitory receptors with MHC-I molecules (HLA-A, -B, -C and –E) on the normal target cell surface. Upon engagement with MHC-I, inhibitory KIR (KIR2DL and KIR3DL) and NKG2A/CD94 receptors become phosphorylated on tyrosine residues within the cytoplasmic ITIM sequences. ITIM phosphorylation leads to the recruitment of SH2 domain-containing phosphatases SHP-1 and/or SHP-2, which dominantly suppress the membrane-proximal tyrosine phosphorylation events to block activation signaling.

Figure 2. Multifactorial diversity of KIR inheritance and expression

A. Inhibitory KIR have separate and sometimes overlapping affinity for distinct HLA molecules. KIR2DL1 has strong affinity for HLA-C2, while KIR2DL2 and KIR2DL3 recognize HLA-C1 with strong affinity and HLA-C2 weakly. KIR3DL1 recognizes Bw4 motifs, but not Bw6 motifs in HLA-B and some -A allotypes, while KIR3DL2 is only known to recognize HLA-A3 and –A11. The ligand interactions are indicated, with wider lines signifying a stronger affinity, while the HLA groups lacking lines (e.g. Bw6 and other A alleles) are not recognized by any KIR. B. KIR genes are inherited in gene arrays named haplotypes of which two major subtypes exist (designated haplotypes A and B). The A haplotypes encode mainly inhibitory KIR (KIR2DL/KIR3DL) with only 1–2 activating KIR (KIR2DL4 and/or KIR2DS4), while the more diverse B haplotypes encode additional activating KIR (KIR2DS/KIR3DS). Representative examples for both haplotypes from four hypothetical human donors are shown with the inherited inhibitory and activating KIR listed. Due to a 22 bp deletion leading to a premature stop codon in a large fraction of KIR2DS4 genes (denoted KIR2DS4), many individuals with A and some B haplotypes fail to express functional KIR2DS4 protein. C. Minor KIR allelic polymorphism can affect both the presence of KIR on the cell surface and their level of surface expression. Many of these minor polymorphisms vary at only one or a few amino acids and it is currently unclear whether some variations also alter HLA recognition. Examples of some KIR2DL4, KIR2DS4, KIR3DL1 and KIR3DL2 alleles that affect expression are shown. D. The variegated expression of KIR during NK cell differentiation will generate a pool of NK cells that is heterogeneous for KIR expression and NK cell activity. In this example, a person lacking expression of HLA-C2 would generate a hyporesponsive NK cell if KIR2DL1 was the only inhibitory receptor expressed on an individual NK cell (no self-recognition). In contrast, NK cells that express inhibitory KIR for which ligand is present (KIR2DL2, KIR3DL1), would become fully functional (self-recognition). Adding to the complexity, Fauriat et al. showed that KIR3DL2 was unable to license NK cells, indicating that an NK cell only expressing KIR3DL2 as a self-recognizing receptor would also be hyporesponsive. Due to their low affinity, interactions between activating (“S”) KIR and HLA are not indicated.