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CHAPTER 17 Cytotoxic T Lymphocytes and Natural Killer Cells 255

also express KIRs after activation, in particular in response NK cells to monitor the expression of multiple MHC class I
to IL-15. proteins using HLA-E as a surrogate, with a prominent example
KIRs recognize the human MHC class I molecules human being the requirement of CD94 for the control of mouse ectro-
leukocyte antigen-A (HLA-A), -B, and -C (see Table 17.2). 20,21 melia virus. 25
The specificity of the inhibitory KIRs has been extensively
characterized, with, for example, the different isoforms of KIR2D NKG2D
recognizing all known alleles of HLA-C. The ligands of the NKG2D, which is only distantly related to the NKG2 family, is
activating KIRs are less clear; however, they do not bind with a single, nonpolymorphic gene that is expressed on all NK cells
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high affinity to HLA molecules. KIR2DL4 is the most evolution- from an early stage. In the mouse, NKG2D signals through
arily distinct member of the family and appears to be expressed both DAP12 and another adaptor, DAP10, whereas human NK
in all activated NK cells in culture and on the CD56 bright subset cells use only DAP10. Activation of NKG2D using a specific
in peripheral blood. KIR2DL4 also has some distinct structural antibody results in enhanced cytotoxicity and cytokine secretion.
features and may act as an unconventional activating receptor The ligands of NKG2D are a family of molecules with structural
binding HLA-G. similarity to MHC class I proteins, including MICA/B in humans
There are epidemiological data implicating particular KIR in and RAE-1 in mice. These ligands represent a diverse array of
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a variety of autoimmune pathologies and viral responses. For sequences, yet all bind with high affinity to NKG2D. Interestingly,
example, individuals with KIR2DS2 and some HLA-C alleles the MIC family in humans is highly polymorphic, suggesting
are predisposed to rheumatoid arthritis with vascular complica- that in this receptor–ligand interaction, the diversity comes from
tions. Conversely, individuals with human immunodeficiency ligands rather than receptors. Transfection of otherwise resistant
virus (HIV) infection who are homozygous for HLA-Bw4 progress tumor cells with NKG2D ligands restores the susceptibility of
to acquired immunodeficiency syndrome (AIDS) more slowly these cells to NK-cell cytotoxic function. The key to understanding
than those with other haplotypes, especially when they have the NKG2D function lies in the fact that the ligands are inducible
KIR3DS1 gene. The mechanism by which this occurs is unknown, and provide a mechanism for NK cells to detect stressed tissue,
but the activity suggests that KIRs recognize an HIV-associated such as virally infected or malignant cells, a phenomenon that
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peptide in the context of HLA-Bw4. 23 has been termed altered self (see Fig. 17.5). Conversely, certain
cancers have been found to mutate or lose NKG2D ligand expres-
The Ly49 Family in Rodents sion to evade NK cell immunity.
In a remarkable example of the power of selection to shape
the evolution of the immune system, a multigenic locus with NK CELL RECEPTORS THAT RECOGNIZE
functional properties almost identical to those of the KIR genes NON-MHC I MOLECULES
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evolved independently in rodents. Mice, which have only two
KIR genes of unknown function, have an analogous cluster of Beyond the multiple systems of activating and inhibitory receptors
type II transmembrane spanning lectin-like genes called the that NK cells have evolved to recognize MHC class I molecules
20
Ly49 family on chromosome 6. This family consists of more and their structural variants, they also have several other receptor
than 20 members and is highly polymorphic between mouse families that bind non–MHC class I ligands. 20,22 These include
strains. Like KIR molecules, Ly49 receptors are also highly the NKR-P1 family, which is a polymorphic multigene family
variegated in their expression in NK cells. Ly49 genes encode in rodents consisting of activating (A, C, F) and inhibitory (D)
activating and inhibitory receptors that bind to MHC class I forms, but consists of only a single member in humans, whose
molecules and signal via ITAMs and ITIMs, respectively (see activity is inhibitory. The ligands for some family members have
20
Table 17.2). Ligand-binding studies have revealed that inhibi- been recently reported and are themselves lectin family receptors,
20
tory Ly49 receptors, such as A, C, and I, function to prevent including Clr-b and Clr-g in mice and LLT1 in humans. Another
self-reactivity by NK cells by binding to MHC class I molecules. NK receptor that is conserved between species is CD244 (2B4),
The function of the activating receptors has proven more difficult a pan-NK-cell–expressed molecule whose ligand is CD48. Based
to elucidate. Ly49D is known to have high affinity for the MHC on antibody cross-linking studies, human CD244 is designated
d
class I H-2D allele and is involved in rejecting bone marrow an activating receptor. However, analysis of CD244-deficient mice
d
allografts expressing H-2D , but the function of Ly49D in the suggests that the mouse homolog is inhibitory. A number of
normal immune response is unclear. For one activating receptor, additional activating receptors exist, including the natural
Ly49H, the physiological function is known, as it recognizes cytotoxicity receptors NKp30, NKp44, and NKp46. NKp30 and
the m157 molecule of MCMV and is important in early viral NKp46 are broadly expressed on human NK cells, and NKp46
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control. 24 is expressed on all mouse NK cells. NKp44 is specifically
expressed on activated human NK cells. These receptors can be
CD94 and NKG2 Family activated by antibody cross-linking, and although their ligands
Unlike the KIR or Ly49 families, the CD94/NKG2 complex is are unknown, there is evidence that NKp46 binds hemagglutinin
present both in rodents and humans. CD94/NKG2 receptors on influenza virus–infected cells, to Fusobacterium nucleatum
recognize nonclassic MHC class I ligands, such as HLA-E in and yet to be determined ligands on tumors, indicating that
b
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humans and Qa1 in mice. A single CD94 gene is physically NKp46 may have a direct role in NK-cell activation to various
linked to four NKG2 (A, C, E, and a truncated F) genes in humans. pathogens. 27
CD94 is found on the cell surface, either alone or with activating
(C, E) or inhibitory (A) forms of NKG2. Interestingly, both the NK-CELL LICENSING AND SELF-TOLERANCE
activating and the inhibitory complexes recognize HLA-E, which
present predominantly the leader peptides of other HLA molecules, The plethora of MHC class I–binding inhibitory receptors, as
but not HLA-E itself. This system may provide a mechanism for proposed by the missing-self hypothesis, explains the influence of