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242 Part III Immunologic Basis of Hematology

either inhibitory or activating, a functional feature associated with signal transduction of other CTLR systems. NKG2D is constitutively
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the intracellular tyrosine-based motif of the molecule. All of this expressed on all NK cells, γδ T cells, and CD8 T cells. 56
information may be deduced for a particular receptor through the NKG2D mediates killing of cellular targets expressing two
nomenclature used to identify KIRs. The number of immunoglobulin- antigens associated with viral or neoplastic transformation. 45,57 First,
like domains (two or three) is expressed (e.g., KIR2D or KIR3D), MHC class I chain–related antigens (MICs) are a family of proteins
and the length of the intracytoplasmic tail (i.e., a long [L] inhibi- whose expression correlates with heat shock and viral and neoplastic
tory tail or a short [S] activating tail) is also incorporated (e.g., transformation. 56,58 MICA and MICB expression is under the control
KIR2DL or KIR2DS). A suffix numeral follows the identification of promoter elements similar to those of heat shock proteins and
of some KIR to represent polymorphic forms of each receptor (e.g., has been shown to be upregulated in the setting of cytomegalovirus
KIR2DS2 and KIR2DS3, each indicating a polymorphic form of an (CMV) infection as well as in a number of epithelial and hematologic
activating KIR that bears the same extracellular domains). HLA-C malignancies. 58,59 Second, UL16 binding protein (ULBP) serves as
is particularly important in KIR-mediated self/nonself recognition a ligand for NKG2D. UL16 is a type I transmembrane protein
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because many well-described KIR have ligand specificity for HLA-C ubiquitously expressed in the setting of CMV infection. UL16
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associated antigens. For example, the inhibitory receptor KIR2DL1 binds MICB and two other proteins, ULBP-1 and ULBP-2. (These
(CD158a) recognizes group 2 HLA-C Asn77Lys80 (HLA-Cw2, w4, latter proteins have α 1 and α 2 domains but lack an α 3 domain as MIC
w5, w6, and related alleles), and the inhibitory receptors KIR2DL2 and MHC class I molecules have; furthermore, they are expressed via
and KIR2DL3 recognize group 1 HLA-C Ser77Asn80 (HLA-Cw1, a glycosylphosphatidyl inositol anchor and thus have no requirement
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w3, w7, w8, and related alleles). Activating receptors KIR2DS1 and for β 2 microglobulin.) In binding MICB, ULBP-1, and ULBP-2,
KIR2DS2 recognize the same group 2 and group 1 antigens as the CMV-produced UL16 counteracts cell surface expression of these
inhibitory counterparts; however, generally, inhibitory receptors bind NKG2D ligands, thus providing a mechanism of immune evasion
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with greater avidity or attraction for a corresponding HLA antigen from NK cell surveillance and cytotoxicity. In a similar fashion,
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than activating receptors. Complementary activating and inhibitory some human tumors downregulate expression of NKG2D ligands or
KIRs recognize the same cognate extracellular domains on target release soluble forms of such (e.g., MICA or ULBPs) as a mechanism
cells; thus, if an NK cell expresses both activating and inhibitory of immune escape from NK cells. 63–65 Although ULBPs are expressed
KIR for an identical ligand, the cell will generally be inhibited from more ubiquitously than MIC proteins, some tissues with high mRNA
killing. levels express no protein, implying important posttranscriptional
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The KIR family is likely not all-inclusive for human classical control of these antigens. IL-15 stimulation enhances the NK cell
type I HLA allotypes; for instance, only one inhibitory KIR directed NKG2D-mediated response to tumors expressing ULBP. 66
against HLA-A (KIR3KL2) and none toward HLA-B alleles have
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been found. Additionally, specific KIRs may have particular roles
in maintaining host immunity in unique settings. For example, Other Activating Natural Killer Receptors
KIR2DL4 recognizes the nonclassical HLA-G molecule that is
expressed only on fetal extravillous trophoblasts that invade the A third family of NK receptors that mediate cell killing are called
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maternal decidua during pregnancy. Controversy surrounds the natural cytotoxicity receptors (NCRs). 59,67 In addition to NKG2D,
exact nature of this KIR; however, KIR2DL4 is likely not clonally NCRs comprise an important family of activating NK cell receptors
distributed as are other KIRs but is present on the surfaces of most involved in the process of target recognition and elimination. NCRs
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mature NK cells. Interestingly, despite having an inhibitory intracel- include three receptors called NKp46 and NKp30, which are exclu-
lular signaling moiety, KIR2DL4 serves to promote IFN-γ secretion sively and constitutively expressed on NK cells, and NKp44, which
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but not cytolytic activity. It is possible that this KIR functions to is expressed after IL-2 stimulation on NK and some γδ T cells. 59,67,68
facilitate immune tolerance to developing fetuses. 49 Infectious, pathogen-specific ligands for NCR have been identified
that recognize and engage various virus-specific hemagglutinin and
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hemagglutinin-neuraminidase. B7-H6 has been identified as a
C-Type Lectin Receptors ligand for NKp30 and a number of other endogenous ligands, and
bacterial and parasite-derived proteins have been described in some
CTLRs, located on human chromosome 12p.12.3, share a common settings as NCR ligands as well. 70–73
subunit (CD94) covalently bonded to one of four closely related gene
products of the NKG2 family. 50,51 CTLRs represent a second type of
NK cell receptor–mediating killing and include NKG2A (and splice ADAPTIVE IMMUNE PROPERTIES OF
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variant B), NKG2C, NKG2E (and splice variant H), and NKG2F. NATURAL KILLER CELLS
NKG2D, which does not bind CD94 and shares little sequence
homology to other NKG2 proteins, is discussed later. All but one of Recent findings regarding NK cell biology are blurring the functional
the CTLRs are activating and expressed on NK cells and cytotoxic borders between the innate and adaptive arms of the immune system.
T lymphocytes. CD94/NKG2A is inhibitory and is expressed on Although NK cells have traditionally been dichotomized in the innate
NK cells, as well as on cytotoxic T lymphocytes, where they serve to immune system, emerging data suggest that NK cells demonstrate
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regulate CD8 T-cell antiviral responses. CD94/NKG2A specifically sophisticated adaptive properties and do not interact in an invariant
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recognizes the nonclassical HLA-E class I molecule. Interestingly, manner in the microenvironment. 74
HLA-E specifically presents leader peptides from other HLA receptor
antigens; thus sensitivity to HLA-E provides a mechanism for NK
cells to sense functional overexpression of class I MHC molecules Natural Killer Cell Education
on cell surfaces. As with KIR, binding between CD94/NKG2A and
HLA-E is more avid than binding of activating CTLRs to other The potential for NK cell autoreactivity exists because some NK
epitopes; however, unlike KIR, the target antigens for activating and cells may lack inhibitory receptors, but others may express activating
inhibitory CTLR are not the same. 54 receptors for self ligands. This can occur because the receptor array
NKG2D is a CTLR; however, it has only modest sequence that individual NK cells express occurs largely at random and because
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homology with other members of the NKG2 family and does not ligands to these receptors are inherited independently. Potentially
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associate with CD94. NKG2D exists as a homodimer and does autoreactive NK cells are not clonally deleted but rather rendered
not have inherent signaling capability, but rather signals via the hyporesponsive. For example, NK cells lacking inhibitory receptors
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PI3K pathway as recruited through DAP10Wu or KAP10. This for self MHC are unresponsive to self cells. In a complementary
unique signal transduction arrangement renders NKG2D signaling manner, humans who lack MHC class I expression do not experi-
privileged from inhibitory, intracellular intermediaries that modulate ence NK cell–mediated autoimmunity. By comparison, through an