Key Concepts:

Figure 1. The three lymphocyte lineages. The figure depicts the characteristic NK cell morphology and phenotype which distinguish these cells from T- and B cells.

Figure 2. The model of missing self. A simplified version of the NK cell strategy for discriminating between healthy and diseased cells. (a) NK cells express inhibitory receptors for autologous major histocompatibility complex (MHC) class I molecules which turn off NK-cell responses to healthy cells expressing normal levels of class I molecules on their surface. (b) When class I expression is lost following viral infection or transformation, these receptors no longer engage their inhibitory ligands, the NK cells are freed from this negative regulation and the host cell is killed. The inhibitory receptor depicted is a member of the KIR (killer cell inhibitory receptor) family, although the other class I receptors (CD94:NKG2 and Ly49) function similarly. The triggering receptors (NKTR) and their ligands (NKTR-ligand) on potential target cells (green) are more heterogeneous and are less critical than the inhibitory receptors and their class I ligands (red) in controlling the outcome of the NK–target interactions.

Figure 3. The NK cell–target cell ‘zipper’. NK cell activation programs result from the integration of multiple activating and inhibitory signals that vary depending on the nature of the interacting cells. These signals involve ITAM (immunoreceptor tyrosine-based activation motif)-bearing molecules and other stimulatory receptors and adhesion molecules, as well as ITIM-bearing inhibitory receptors. Some human (left) and mouse (right) receptor–ligand interactions are depicted here, to illustrate the combinatorial nature of the NK cell interaction repertoire. Cytokines, chemokines and their receptors are not shown, but are also crucial for the regulation of NK cell functions. Inhibitory receptors are in blue; 2B4, which can act as an activating or an inhibitory molecule, is in grey; other receptors are in green. Vertical lines indicate the receptor–ligand pairs conserved between mice and humans, which consist either of real orthologues (e.g. human and mouse NKp46) or examples of convergent evolution (e.g. KIR and Ly49). KIR, killer immunoglobulin-like receptors; LIR, immunoglobulin-like transcript; LAIR, leukocyte-associated immunoglobulin-like receptor; SIGLEC, sialic acid-binding immunoglobulin-like lectins; KLRG-1, killer cell lectin-like receptor G1; NKR-P1, NK cell receptor protein 1; HLA, human leukocyte antigen; LLT, lectin-like transcript; CRTAM, class I restricted T cell–associated molecule; Necl-2, nectin-like 2; Tactile (also known as CD96), T cell-activated increased late expression; CEACAM1, carcinoembryonic antigen-related cell adhesion molecule 1; PILR, paired immunoglobulin-like type 2 receptor; NTB-A, NK-T-B antigen; CRACC, CD2-like receptor-activating cytotoxic cell; VCAM-1, vascular cell adhesion molecule 1; ICAM, intercellular adhesion molecule; Ocil, osteoclast inhibitory lectin. Please note ‘?’ indicates that additional ligands might exist. Reproduced from Vivier et al. (2008) with permission from Nature Publishing Group.

Figure 4. Positive and negative signalling pathways in NK cells. Positive signalling cascades in NK cells and other lymphocytes are dependent on the activation of various protein tyrosine kinases (PTKs). The inhibitory receptors counteract the actions of the PTK-driven activation pathways through their recruitment of cytoplasmic tyrosine phosphatases (SH2 domain-containing phosphatase (SHP)-1 and -2). Once recruited to the phosphorylated ITIMs, SHP-1 and -2 become enzymatically active and dephosphorylate PTK substrates such as immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor chains, downstream PTK, other signalling enzymes (phospholipases) and adapter proteins. Through these antagonistic dephosphorylating events the inhibitory receptor/SHP complex can shut off NK-cell activation. Green arrows indicate positive signalling pathways and red arrows indicate negative ones.