Natural killer (NK) cells are defined by the expression of CD16 and CD56 surface molecules. In peripheral blood, two populations of NK cells are present. One population comprises large granular lymphocytes that are phenotyped as CD3–, CD16+, CD56+, and CD94+ cells. Since they do not express T or B cell markers, they are considered to be of a third lymphocyte lineage. The second population of NK cells comprises T cells that express both T cell and NK cell markers (CD3+, CD16+, CD56+ or CD3+, CD16–, CD56+). These cells are known as natural killer T cells (NKT cells) to differentiate them from large granular lymphocytes.

NK and NKT cells have different functions. NK cells are part of the innate cell-mediated response to infected or tumor cells. They recognize and lyse cells with downregulated human leukocyte antigen (HLA) class I molecules. In contrast to classic NK cells, NKT cells have limited cytolytic capability and require antigen presentation. Emerging evidence also suggests that NKT cells are involved in immediate allergic reactions, suppression of auto-reactive lymphocytes, and tumor immunity. Activation or inhibition of NK and NKT cells is dictated by interactions between cell receptors and HLA class IB molecules or CD1 molecules on target cells.

Natural Killer Cell Receptors

CD94–NKG2 Receptors

The most studied NK cell receptor is CD94—a type 2 “lectin-like” receptor expressed on both NK cells and cytotoxic T cells (CTLs). To create an active receptor, CD94 pairs with NKG2A, B, C, E, or F. NK cell function is dictated by different pairings between CD94 and NKG family members. For example, NKG2A and NKG2B dimerize with CD94 and inhibit NK cell function. Conversely, CD94–NKG2C dimers activate NK cells (Figure 21-1).

Figure 21-1 Inhibitory receptors consist of CD94 disulfide-bonded (*red*) to peptides from the *NKG2* locus, such as NKG2A, which have intracellular domains carrying ITIMs (immunoreceptor tyrosine-based inhibitory motifs). Noninhibitory receptors (such as CD94/NKG2C) lack ITIMs but have a charged lysine residue (K) in the transmembrane segment that allows them to interact with signal-transducing molecules. (From Roitt I, Brostoff J, Male D, et al: Immunology, ed 7, Philadelphia, 2006, Mosby.)

Killer Cell Immunoglobulin-Like Receptors

Killer cell immunoglobulin-like receptors (KIRs) are encoded by a family of 15 polymorphic genes and two pseudogenes on chromosome 19. KIRs are membrane anchor proteins that possess either two (KIR2DS) or three (KIR3DS) immunoglobulin domains (Figure 21-2).

Within each subfamily, KIRs that inhibit or activate NK cells are present (Table 21-1).

Table 21-1

Immune Receptors Encoded by Genes in the Leukocyte Receptor Complex Region

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Names	CD	Function	Signaling	Ligand
KIR3DL3	CD158z	Inhibition	ITIM
KIR2DL3	CD158b2	Inhibition	ITIM	HLA-C S77/N80
KIR2DL2	CD158b1	Inhibition	ITIM	HLA-C S77/N80
KIR2DL1	CD158a	Inhibition	ITIM	HLA-C N77/K80
KIR2DS1	CD158h	Activation	DAP12	HLA-C, weakly
KIR2DS2	CD158j	Activation	DAP12
KIR2DS4	CD158i	Activation	DAP12	HLA-C, weakly
KIR3DL2	CD158k	Inhibition	ITIM	HLA-A
KIR2DL3	CD158i	Inhibition	ITIM	HLA-C

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HLA, Human leukocyte antigen; ITIM, immunoreceptor tyrosine-based inhibitory motifs; KIR, killer cell immunoglobulin-like receptor.

Modified from Cooper MD, Lewis LL, Conley, ME, et al: Immunodeficiency disorders. American Society of Hematology Education Program, pp. 314–330, 2003. Hematology 2003, The American Society of Hematology.

Target Cell Recognition Molecules

NK cells do not detect aberrant or infected cells. Rather, they recognize cells that lack HLA class I molecules. This observation has led to the development of the “missing self” hypothesis of NK cell activation. The hypothesis suggests that NK cells can kill normal cells but are prevented from doing so by the presence of inhibitory factors such as HLA class I markers. Downregulation of class I molecules allows NK cells to engage other molecules that either activate or inhibit the NK cell.

HLA-E, a nonclassic HLA locus, is the natural ligand for CD94–NKG2A and B complexes. HLA-E binds the peptide leader sequence from HLA-G. The HLA-G sequence is encoded upstream of the open reading frame for the α-chain. In the cytoplasm, the N-terminal fragment of the leader sequence is released after cleavage by signal peptidases and endoplasmic reticulum (ER) proteases. The small leader peptide is loaded into the binding groove in the ER and transported to the cell surface (Figure 21-3).