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Chapter 101 Natural Killer Cell–Based Therapies 1577

end, KIR3DL2 at the telomeric end and KIR2DL4 in the middle. and gain of function. Conversely, adoptive transfer of fully functional
The A KIR haplotype contains a fixed content of genes that also NK cells from wild-type mice into β2-microglobulin knockout hosts
includes the inhibitory receptors KIR2DL1, KIR2DL3, and results in NK hyporesponsiveness. 9,10 Collectively, these data support
KIR3DL1 along with a single activating receptor (KIR2DS4). In the model of NK cell education as a dynamic, inherently plastic
contrast, B KIR haplotypes contain a variable number of activating process where low level, tonic inhibitory signals are required to
(KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, KIR3DS1) and inhibi- maintain cytotoxic capacity. It has also been demonstrated that the
tory (KIR2DL5A/B, KIR2DL2) genes. KIR2DL2/3 and KIR3DL1/S1 cumulative strength of inhibitory receptor signaling correlates with
are genes whose alleles determine whether they define KIR A functional thresholds. This model, aptly compared to a “rheostat,”
(KIR2DL2 and 3DL1) or KIR B (KIR2DL3 or KIR3DS1) permits self-tolerance in the normal state and allows for enhanced
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haplotypes. sensitivity to damage to healthy cells through class I downregulation.
Inhibitory KIR recognizes self-class I human leukocyte antigen Importantly, it must be emphasized that not all acquisition of NK
(HLA) molecules on potential target cells. This interaction sup- cell function is through NK cell education. NK cells can overcome
presses the NK cell effector responses. Inhibitory KIR recognizes rules of NK cell education in the presence of high concentrations
polymorphisms of HLA-C and B in a biallelic manner (i.e., C1 of cytokines, in settings such as in vitro activation where exogenous
versus C2 and Bw4 versus Bw6). KIR2DL1, KIR2DL2/KIR2DL3 cytokines are applied or during inflammatory conditions where high
and KIR3DL1 bind HLA class I C2, C1, and Bw4 alleles, respec- levels of cytokines are present. In the mouse, the importance of
tively. These inhibitory receptor–ligand interactions are complex, as inflammation-induced cytokine production leading to enhanced NK
the mere expression of the receptors does not predict the cellular function is clearly demonstrated by the ability of NK cells from
response. Rather, the affinity of a given KIR seems to depend on β2-microglobulin knockout mice, which are hyporesponsive in
allelic polymorphisms both of KIR and its MHC class I ligand. vitro, to clear murine CMV. In summary, NK education determines
In addition, the receptor–ligand binding rules are not absolute, as the function of NK cells at steady state, but other factors may
KIR2DL2 can bind both HLA-C1 and HLA-C2 alleles. KIR also overcome or even dominate, especially when cytokines are admin-
binds to HLA-A alleles (A3 and A11) that contain the Bw4 epitope, istered to patients or used to stimulate NK cells that are adoptively
and KIR3DL2 binds some HLA-A alleles in the context of certain transferred.
peptides. Our understanding of the KIR system is further complicated
by the fact that the natural ligands for activating KIR remain largely
unknown. Although some bind MHC molecules at low affinity, it is Natural Killer Cell Recognition of Tumors
not known whether MHC proteins function as the natural ligands
in vivo. Although KIR2DS1 has been shown to bind HLA-C2, Although the antitumor efficacy of NK cells has been most evident
KIR2DS2 does not bind HLA-C1 but recently has been shown to for myeloid malignancies, a wide variety of solid tumors includ-
recognize threonine 80 of HLA-A11, which can be modified by ing breast, ovarian, hepatocellular, colon, neuroblastoma, Ewing
peptide. 5 sarcoma, rhabdomyosarcoma, and melanoma can be sensitive to NK
cell lysis. The relative resistance of some tumors may be caused
by a higher expression of class I HLA, which inversely correlates
Additional Natural Killer Cell Receptors with the susceptibility of primary pre–B cell acute lymphoblastic
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leukemia (ALL) blasts to NK cell lysis. Successful destruction of a
Several other families of activating and inhibitory receptors influence target requires coengagement of NK cell receptors by both inhibi-
NK cell function, some of which bind HLA molecules. The NKG2 tory and activating signals. Accordingly, activating receptors such as
family of C-type lectin receptors that heterodimerize with CD94 may NKG2D play an important role in immune surveillance and killing
be either inhibitory (NKG2A) or activating (NKG2C), and can of acute myeloid leukemia (AML) stem cells. Other tumor ligands
recognize nonclassic HLA-E. NKG2D does not heterodimerize with that correlate with responsiveness to NK cell-mediated killing include
CD94 and recognizes stress-induced molecules such as MHC class I DNAM-1 on myelodysplastic syndrome blasts, CD137 ligand on
polypeptide-related sequence A/B (MICA and MICB) or viral-derived AML targets, and B7-H3, which protects neuroblastoma from NK
proteins like the CMV-related UL binding proteins (ULBP1-6). lysis. When considering therapeutic uses of NK cells and interven-
Additional receptors include the natural cytotoxicity receptors tions such as the use of anti-KIR or anti-NKG2A antibodies to
NKp30, NKp46, and NKp44, DNAM-1, and Nectin-2 (CD122), promote tumor lysis, it is important to remember that many NK
2B4, Ig-like receptors, and leukocyte-associated immunoglobulin- cells circulating in steady-state peripheral blood variably express
like receptor-1. These activating receptors are believed to play a role KIR and NKG2A. Therefore maximum killing of targets such as
in communication between NK cells and dendritic cells as well as leukemia blasts may require blockade of multiple inhibitory receptor
determining whether an NK cell can recognize a target. interactions.

Natural Killer Cell Education—The Acquisition of Innate Lymphoid Cells
Function, Self-Tolerance, and Alloreactivity
Until recently, NK cells were the only known lymphocyte population
A mechanistic explanation for the phenomenon of “hybrid resistance” that could be considered “innate lymphoid cells.” However, more
and “missing self” is derived from the characterization of NK cell recently, it has been appreciated that there are a variety of different
inhibitory receptors that recognize self-MHC class I. In both instances, innate lymphoid cell (ILC) populations, known as ILC1, ILC2, and
because they fail to engage inhibitory receptors, target cells lacking ILC3 cells. Similar to the T-cell paradigm, ILCs have been categorized
self-MHC class I expression are sensitive to NK-mediated killing. by key transcription factor expression, which drives unique cytokine
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Thus NK cells detect either allogeneic cells or disease-associated production in response to activation. More specifically, ILC1 cells
downregulation/loss of MHC class I on virally infected or tumor (including NK cells) are characterized by T-bet expression and
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cells. The process of inhibitory receptor signaling that leads to the produce IFN-γ in response to the monocyte-derived cytokines IL-12
acquisition of cytotoxicity and cytokine production has been referred and IL-18. ILC2 cells express GATA-3 and produce IL-5 and IL-13
7,8
to as “NK cell education” or “NK licensing.” NK cells lacking both following stimulation with IL-25 and IL-33, and ILC3 cells express
KIR and NKG2A are hyporesponsive and cannot be educated until the transcription factor ROR-γt and produce IL-22 in response to
inhibitory receptors are expressed. Relevant to the field of allo-HCT, IL-1 and IL-23 stimulation. The physiologic role for these cells, both
NK cell education may not be fixed. For instance, adoptive transfer in health and pathology is still emerging, but recent studies suggest
of hypofunctional NK cells from β2-microglobulin knockout mice that ILC1 cells play a role in anticancer responses and ILC2 and ILC3
(that lack MHC class I) into wild-type mice leads to their education cells may assist in response to pulmonary and intestinal pathogens